Next Article in Journal
Rilpivirine Activates STAT1 in Non-Parenchymal Cells to Regulate Liver Injury in People Living with HIV and MASLD
Previous Article in Journal
The Hydroxypyridinone Iron Chelator DIBI Reduces Bacterial Load and Inflammation in Experimental Lung Infection
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

p53 Genetics and Biology in Lung Carcinomas: Insights, Implications and Clinical Applications

by
Dixan A. Benitez
*,
Guadalupe Cumplido-Laso
,
Marcos Olivera-Gómez
,
Nuria Del Valle-Del Pino
,
Alba Díaz-Pizarro
,
Sonia Mulero-Navarro
,
Angel Román-García
and
Jose Maria Carvajal-Gonzalez
*
Departamento de Bioquímica, Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, 06006 Badajoz, Spain
*
Authors to whom correspondence should be addressed.
Biomedicines 2024, 12(7), 1453; https://doi.org/10.3390/biomedicines12071453
Submission received: 16 May 2024 / Revised: 20 June 2024 / Accepted: 26 June 2024 / Published: 29 June 2024
(This article belongs to the Section Cell Biology and Pathology)

Abstract

:
The TP53 gene is renowned as a tumor suppressor, playing a pivotal role in overseeing the cell cycle, apoptosis, and maintaining genomic stability. Dysregulation of p53 often contributes to the initiation and progression of various cancers, including lung cancer (LC) subtypes. The review explores the intricate relationship between p53 and its role in the development and progression of LC. p53, a crucial tumor suppressor protein, exists in various isoforms, and understanding their distinct functions in LC is essential for advancing our knowledge of this deadly disease. This review aims to provide a comprehensive literature overview of p53, its relevance to LC, and potential clinical applications.

1. Introduction

p53 protein is a critical tumor suppressor, maintaining genome stability and inhibiting tumorigenesis in the cell. The primary function of p53 is to act as a transcriptional activator for a diverse array of genes by recognizing and binding to specific DNA sequences [1]. Additionally, the p53 network plays a role in contributing to adaptive homeostasis [2,3]. Under normal conditions, p53 levels are downregulated by MDM2 and MDMX. However, in response to stimuli such as DNA damage, ribosomal stress, metabolic stress, and other conditions, p53 undergoes post-translational modifications to swiftly stabilize and subsequently activate genes with diverse cellular functions [4], as shown in Figure 1. Consequently, the p53 protein transcriptionally activates genes that play a decisive role in determining the cell’s fate—whether it survives or undergoes programmed cell death [5]. The mutation in p53 is acknowledged as one of the most common concurrent genomic alterations in non-small-cell lung cancer (NSCLC). Despite the establishment of an oncogene-centric molecular classification paradigm for this lung cancer [6], the precise role of p53 in NSCLC remains unclear, particularly in two of its primary subtypes with distinct cellular origins, namely, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).

Other Relevant Tumor Suppressors

p53, Rb1 (retinoblastoma 1), and PTEN (phosphatase and TENsin homolog) are three key tumor suppressor genes that play critical roles in maintaining genomic stability and preventing the development of cancer. While they share some common functions, each tumor suppressor also possesses unique characteristics that contribute to their specific roles in cancer biology. As mentioned before, p53 is often referred to as the “guardian of the genome” due to its central role in regulating cell cycle progression, DNA repair, apoptosis, and senescence in response to various cellular stresses, including DNA damage and oncogenic signaling. It acts as a transcription factor, regulating the expression of genes involved in these processes [7,8,9,10,11].
Rb1, on the other hand, functions primarily in regulating the cell cycle by inhibiting the activity of the E2F family of transcription factors. By binding to E2F, Rb1 prevents the expression of genes required for S-phase entry, thereby halting cell cycle progression and promoting cell cycle arrest or apoptosis. Dysfunction of Rb1 is associated with a wide range of cancers, particularly retinoblastoma, osteosarcoma, and small-cell lung cancer [12]. PTEN functions primarily as a lipid phosphatase that antagonizes the PI3K/AKT/mTOR signaling pathway, thereby regulating cell growth, proliferation, and survival. By dephosphorylating phosphatidylinositol (3,4,5)-trisphosphate (PIP3), PTEN suppresses downstream signaling events that promote cell survival and proliferation. Loss of PTEN function is frequently observed in various cancers, including glioblastoma, prostate cancer, and endometrial cancer [13]. While all three tumor suppressors play crucial roles in preventing cancer development, they exhibit both overlapping and distinct functions. For example, p53 and Rb1 both regulate cell cycle progression, albeit through different mechanisms, whereas PTEN primarily regulates cell growth and survival signaling pathways. Additionally, all three tumor suppressors can induce apoptosis, although p53 is perhaps best known for its role in this process. Dysfunction of any of these tumor suppressors can lead to uncontrolled cell proliferation and tumorigenesis, underscoring their importance in maintaining cellular homeostasis and preventing cancer [11,14,15,16].

2. p53: Gene and Protein

The TP53 tumor suppressor gene (NG_017013) is situated in chromosome 17 at the short arm (17p13.1) and comprises 13 exons, with the first being noncoding [17]. Highly conserved in multicellular organisms [18], the TP53 gene exhibits numerous genetic polymorphisms, describing over 100 different haplotypes of TP53. Some of these haplotypes are associated with an elevated risk of cancer [19,20,21]. Previous studies have identified TP53 as the most frequently mutated gene in human cancers [22,23,24,25,26,27,28,29]. Despite this recognition, translating TP53 mutation status into effective cancer treatment and predicting clinical outcomes remains challenging in the clinical setting. This highlights that our comprehension of the p53 pathway is not yet exhaustive. The identification of various splice variants encoded by the TP53 gene may provide an explanation for this discrepancy [17].
The TP53 gene stands out as one of the most extensively studied genes in recent decades [30]. For many years, it was commonly believed that human TP53 exclusively expressed a single protein, p53. However, in 2005, Burdon et al. revealed that the TP53 gene expresses a minimum of 12 isoforms of p53 in humans [31]. TP53 is expressed not only as the full-length p53 (FLp53, canonical p53, wild-type p53, or p53α) but also as 11 smaller isoforms: p53β, p53γ, ∆40p53α, ∆40p53β, ∆40p53γ, ∆133p53α, ∆133p53β, ∆133p53γ, ∆160p53α, ∆160p53β, and ∆160p53γ [31,32,33]. These isoforms are produced via processes such as alternative splicing, alternative initiation of translation, alternative promoter usage, or post-translational degradation of p53 through the 20S proteasome [31,32,34,35,36].
At the protein level, full-length p53 is characterized by distinct functional domains. These include two transactivation domains (TADs) at the N-terminus, a proline-rich domain (PRD), a central DNA-binding domain (DBD), an oligomerization domain (OD), and a regulatory C-terminal domain (CTD) at the carboxy-terminal region [37]. The N-terminal segment of the protein encompasses the transactivation domain, housing regions that engage in protein–protein interactions with regulatory proteins, such as MDM2. This interaction initiates ubiquitination, ultimately leading to the degradation of the protein in the proteasome [38,39,40].
At the functional level, the p53 protein acts as a transcription factor contributing to tumor suppression by activating the expression of a multitude of target genes [37]. In the context of cancer, p53 plays a crucial role in restraining cell proliferation in response to a variety of stimuli, which include factors like DNA damage, nutrient scarcity, hypoxia, and hyperproliferative signals, so this function of p53 acts as a barrier against the formation of tumors [41], earning it the well-deserved title of the guardian of the genome. Under normal physiological conditions, MDM2, an E3 ligase, meticulously controls the levels of p53, initiating its degradation through the ubiquitin proteasome-dependent pathway. Furthermore, p53 can induce the expression of MDM2, recognizing and interacting with its promoter region, establishing a negative regulation designed to promote the degradation of p53 and maintain low cellular p53 levels [42]. When the cell faces various stress situations, p53 is subjected to several post-translational modifications, notably phosphorylation, which serves to stabilize p53 as it interferes with the interaction with MDM2. In addition, sequence-specific DNA binding and transactivation may take place. Through these processes, p53 either activates or suppresses target genes involved in regulating the cell cycle, DNA repair, and the induction of senescence and apoptosis [43].
In addition to its dominant-negative activity, which interferes with the functions of wild-type p53, numerous studies have demonstrated that mutations in p53 can afford oncogenic properties through gain-of-function (GOF) mechanisms. In these scenarios, the mutant p53 protein engages with new transcription factors or cofactors, exerting control over gene transcription and expression to facilitate the development of cancer [23,28,44,45,46,47,48,49,50,51].
The TP53 gene has been implicated in an expanding array of biological processes, encompassing cell cycle arrest, apoptosis, DNA repair, autophagy, metabolism, senescence, and aging [1,52,53,54,55,56]. The zinc ion plays a pivotal role as a cofactor for wild-type p53, crucial for its effective binding to DNA. Any mutations affecting the zinc-coordinating residues disrupt the ability of p53 to bind to zinc ions, rendering it incapable of interacting with DNA [57].
Some studies have demonstrated dysregulation in the mRNA expression of p53 isoforms in various cancers [31,58,59,60,61,62,63,64], where the p53 isoforms have been associated with prognosis [62,65] and chemotherapy response [58,59].
Efforts to destabilize mutant p53 and thwart its GOF activities are actively explored as a hopeful therapeutic strategy for cancers with p53 mutations [23,48,66,67,68]. However, the precise mechanisms governing the accumulation of mutant p53 in cancer remain incompletely understood, posing a challenge to the development of effective strategies for treating cancers carrying mutant p53 [69]. Presently, there are no clinically available drugs that target mutant p53 for cancer treatment [23,67,68]. Therefore, gaining a more thorough understanding of the mechanisms responsible for the accumulation of p53 mutants and their GOF activities in cancer is crucial [69].
The most common polymorphisms in the TP53 gene include the following. (1) rs1042522 (p.Arg72Pro or R72P): This polymorphism results in an arginine (Arg)-to-proline (Pro) substitution at codon 72 of exon 4. The Arg72 variant is associated with increased apoptosis and has been linked to a higher risk of certain cancers, such as lung cancer and colorectal cancer. The Pro72 variant is less efficient in inducing apoptosis but may be associated with other cancers like breast cancer. (2) rs1625895 (intron 3): This polymorphism is found in intron 3 of the TP53 gene and can affect splicing or gene regulation. Certain intronic polymorphisms are linked to different cancer risks depending on the population studied. (3) rs17878362 (16-bp Ins/Del): This is a 16-base pair insertion/deletion polymorphism in intron 3. This variation can influence TP53 mRNA splicing and is associated with altered cancer risk [70,71,72].
Specific haplotypes formed by these polymorphisms can either increase or decrease susceptibility to various cancers depending on the population and the type of cancer. Understanding these genetic variations and their functional consequences helps in predicting cancer risk and developing targeted therapies. The Pro72 variant combined with specific intron 3 polymorphisms (such as rs1625895) forms a haplotype that has been linked to a higher risk of developing cancer, particularly in Asian populations [73,74]. The Arg72 variant, when associated with certain other polymorphisms in the TP53 gene, forms a haplotype that might be protective in some cancers but risk-enhancing in others. For example, the Arg72 variant has been associated with increased risk of colorectal cancer but may be protective against other types like bladder cancer. Haplotypes involving the 16-bp insertion/deletion polymorphism (rs17878362) in combination with other TP53 polymorphisms can influence cancer risk. The specific combination can either increase susceptibility or confer protection depending on the cancer type [19,73,75,76,77,78,79,80].

3. LC and p53

TP53 is the most frequently mutated gene in human cancers because it regulates the cell cycle, promotes DNA repair, and initiates apoptosis in response to DNA damage. This makes it a critical barrier to cancer development, as the inactivation of p53 removes a major obstacle to uncontrolled cell division. Tumors often evolve to bypass the growth-inhibitory effects of p53. In addition, the TP53 gene is particularly susceptible to damage from various environmental mutagens and carcinogens. This high exposure increases the likelihood of mutations, and mutations in TP53 can simultaneously disrupt multiple tumor suppressive pathways, including cell cycle arrest, apoptosis, DNA repair, and senescence. This broad impact makes TP53 mutations particularly advantageous for cancer cells [81,82,83].
The main types of TP53 mutations and their effects on cancer development are listed as follows.
Missense Mutations: A single nucleotide change results in the substitution of one amino acid for another in the p53 protein. These mutations often occur in the DBD, leading to a loss of DNA-binding ability and the subsequent loss of transcriptional regulation of target genes. Many missense mutations produce a dominant-negative effect, where the mutant p53 interferes with the function of any remaining wild-type p53, or a GOF effect, where the mutant protein acquires new oncogenic properties. Nonsense Mutations: A single nucleotide change introduces a premature stop codon, resulting in a truncated, non-functional p53 protein. These mutations usually lead to complete loss of p53 function (LOF), as the truncated protein is typically unstable and degraded rapidly, preventing it from exerting any tumor suppressive effects. Frameshift Mutations: Insertions or deletions of nucleotides alter the reading frame of the gene, leading to the production of an aberrant protein. Frameshift mutations generally produce non-functional p53 proteins that are either truncated or have lost critical domains necessary for tumor suppression. These proteins are often degraded or fail to perform their regulatory functions. Splice Site Mutations: Mutations at the junctions of exons and introns affect the splicing of TP53 mRNA. These mutations can lead to the production of abnormal p53 isoforms that either lack essential functional domains or have altered regulatory properties, potentially contributing to cancer progression. Intragenic Deletions: Deletions within the TP53 gene remove entire exons or parts of exons. These deletions often result in truncated p53 proteins that are non-functional and unstable, leading to a complete loss of p53 tumor suppressive activity [81,82,83,84,85,86,87,88].
LC stands as the foremost cause of cancer-related deaths globally [89,90]. As mentioned above, lung cancer is divided into two primary types: small-cell lung cancer (SCLC) and NSCLC. Each year, approximately 2 million new cases of lung cancer are diagnosed, leading to 1.8 million global deaths attributed to the disease [91]. Histopathologically, NSCLC is the predominant type, accounting for 80–85% of all lung cancer cases [92,93,94]. LUSC constitutes around 30% of NSCLC cases, making it the second most prevalent histological type of lung cancer [95].
Dysregulation of p53 often contributes to the initiation and progression of various cancers, including LUSC. In the initiation phase, loss of cell cycle control due to mutations or loss of p53 disrupt its function in arresting the cell cycle and facilitating DNA repair, potentially allowing cells with DNA damage to propagate, initiating tumorigenesis [96,97]. The compromised p53 can reduce apoptosis, permitting survival of transformed cells that might otherwise be eliminated. In this way, p53 inactivation may result in reduced apoptotic potential, allowing the survival of cells with aberrant growth characteristics [98]. In the progression phase, the p53 dysregulation fosters genomic instability, enabling accumulation of additional mutations that may facilitate cancer progression [99]. Altered p53 can influence angiogenesis, fostering a tumor-permissive microenvironment that supports progression. Some studies suggest that p53 mutations may be linked to enhanced invasive and metastatic potential in, e.g., head and neck squamous cell carcinoma, although the precise mechanisms remain to be fully elucidated [100]. Also, mutant p53 can induce epithelial–mesenchymal transition and metastasis, enhancing the migratory and invasive properties of tumor cells [101]. p53 mutations might interact with other oncogenic pathways (like PI3K/AKT and MAPK), further supporting tumor progression and resistance to therapy [102], and may also influence the tumor microenvironment through immune regulatory pathways, potentially enabling tumors to evade immune surveillance [103]. Recently, it has been reported that the regulation of p53 by MDM2 plays an active role in regulating both the self-renewal and differentiation processes of basal stem cells in both mouse and human airway epithelium [104]. On the other hand, a recent publication analyzing Trp53 null and wild-type mice demonstrated that p53 plays a role in directing alveolar regeneration following injury. It achieves this by regulating alveolar type 2 (AT2) cell self-renewal and promoting the transitional differentiation of cells into alveolar type 1 (AT1) cells. The reported results could provide insights into the mechanisms of p53-mediated suppression of LUAD. In this context, p53 appears to play a pivotal role in regulating alveolar differentiation, suggesting that the suppression of tumors might be tied to the essential role of p53 in coordinating tissue repair after injury [105].
The mutation in p53 is acknowledged as one of the most common concurrent genomic alterations in NSCLC. This observation persists despite the establishment of an oncogene-centered molecular classification paradigm for this type of lung cancer [6]. The prevalence of TP53 mutation exceeds 90% in LUSC, and concurrently, the tumor suppressor cyclin-dependent kinase inhibitor 2A (CDKN2A), responsible for cell cycle regulation, is inactivated in approximately 70% of LUSC cases [106]. Nevertheless, the distinct function of p53 in NSCLC, particularly in its major subtypes with distinct cellular origins—LUAD and LUSC—are still to be clarified. Several studies suggest that mutant p53 correlates with unfavorable clinical outcomes [107,108,109], while the activation of p53 signaling or restoration of wild-type p53 has been demonstrated to suppress tumorigenesis [110,111,112]. Nevertheless, elevated expression of the oncoprotein p53 has been proposed as a promising prognostic indicator in a subgroup of patients with NSCLC [113]. In addition, recent research indicates that the existence of mutant p53 is correlated with a shorter survival outcome in patients diagnosed with LUAD and, conversely, in those patients diagnosed with LUSC, significantly longer overall survival [114]. Enhancing our comprehension related to the function of p53 in the progression of these lung cancer subtypes holds the promise of developing a more targeted and rational therapeutic strategy, potentially leading to an extension in the survival of the patient. Despite LUAD and LUSC presenting a distinct biological imprint, their treatment approaches often overlap [94]. In a recent study, it was observed that p53 expression in LUAD and LUSC is linked to distinct activation or suppression pathway profiles. Despite the historical perception of p53 as challenging to directly target, the pathways influenced by p53 expression might offer viable targets for cancer therapy. Additionally, understanding the unique pathways in LUAD or LUSC may guide the development of more precise and subtype-specific cancer therapies in the coming years [115].
The correlation between lung cancer and tobacco use is intricate, with variations observed among histologic subtypes. LUAD primarily manifests in individuals without significant tobacco exposure, while LUSC is predominantly found in current or former smokers [116]. Adding complexity to this association, changes in the composition of cigarettes are believed to contribute to differences not only in the risks associated with smoking and lung cancer but also in the histologic subtypes linked to tobacco exposure [117,118].
The hallmark of cancer often involves significant changes in the epigenetic landscape. Specifically, in LUSC, frequent mutations are observed in genes that encode epigenetic regulators [119,120,121]. Significantly, TP53 mutations were linked to the emergence of new distant metastases. Notably, these mutations were more prevalent among patients with a history of smoking, implying an increased risk of distant metastasis in individuals with such a smoking history [122].
Mutational hotspots are primarily concentrated within the sequence-specific DNA-binding domain, with approximately 75% of mutations being missense alterations, resulting in the loss of its function as a transcription factor [123]. The mutational patterns are influenced by smoking [123,124], and a correlation exists between p53 mutational hotspots and sites of adduct formation by polycyclic aromatic hydrocarbon [125,126]. The build-up of p53 non-functional mutants contributes to increased concentrations of mutated p53 in tumor cells [127].
Utilizing cBioPortal for Cancer Genomics [128,129,130], an open access, open source resource facilitating interactive exploration of multidimensional cancer genomics datasets, we conducted an analysis of the genetic alterations of p53 in various types of lung cancer. As shown in Figure 2a, all lung cancer subtypes show alterations in the p53 gene to different degrees: LUAD 47%, NSCLC 62%, LUSC 81%, and SCLC 86%. Among all the alterations described, putative-driven missense mutations (green tags) occur most predominantly, being particularly important in LUSC, where they account for most of all genetic alterations.
When analyzing the point mutations within the p53 gene in LUSC, mutations are concentrated in the DNA-binding domain (red) with R158L/Asf*12/G being the most abundant among all patients (Figure 2b). Note that missense mutations are also the most common in this domain. Taking together the data in Figure 2a,b, it can be observed that the majority of these missense mutations are located along the DNA-binding domain segment of the p53 gene.

LOF and GOF of p53 in LC

In lung cancer, alterations in the p53 pathway are prevalent, with both LOF of wild-type p53 and GOF promoted by p53 mutants contributing to tumorigenesis and disease progression. Wild-type p53 functions as a tumor suppressor by inducing cell cycle arrest or apoptosis in response to cellular stress, thereby preventing the propagation of damaged cells [131,132]. LOF of p53 is critical for the proliferation, survival, and metastasis of a broad range of cancer cells, including lung cancer [133]. LOF enhances the metastatic potential of LUSC cells through the dysregulation of epithelial–mesenchymal transition markers [134]. Inactivating mutations of the TP53 gene results in the LOF of wild-type p53 and/or dominant-negative p53 mutants. In this respect, studies using mice as the model suggest that certain p53 mutations confer oncogenic GOF activities that promote tumorigenesis and metastasis [135,136]
In contrast to wild-type p53, mutant forms of p53 frequently exhibit GOF properties, conferring oncogenic functions that drive tumorigenesis and therapeutic resistance [137], as shown in Figure 3. In lung cancer, specific p53 mutations are associated with distinct GOF activities, including increased cell proliferation, invasion, and chemoresistance. The majority of gene mutations manifest as missense mutations, primarily found within the DNA-binding functional domain of the p53 gene. Notably, the mutation frequency was highest for six specific amino acid residues in p53: R175, G245, R248, R249, R273, and R282 [138,139]. These mutations allow the p53 protein to potentially engage with non-canonical protein partners, thus facilitating oncogenesis. Interesting, recent data suggest that chloroquine treatment resulted in cytoplasmic accumulation and reduced transcriptional activity of GOF p53 R273H and YAP (Yes-associated protein), leading to growth arrest of NSCLC cells [140].

4. p53: Clinical Applications and Therapies

Addressing the p53 axis has posed challenges because p53, being a transcription factor, involves intricate protein–protein interactions. Unlike more easily druggable targets with accessible receptor–ligand interactions or enzymatic active sites, p53 lacks such characteristics, adding complexity to its therapeutic targeting [141]. Diverse approaches have been explored to target p53, ranging from adenovirus-based gene therapy to the recent development of small molecules designed to activate endogenous p53 in tumors that retain the wild-type p53 gene [127]. A potential strategy involves the development of small molecules to boost p53 activity by neutralizing MDM2, such as nutlins, which bind to MDM2 and dissociate it from p53. Additionally, there are ongoing efforts to develop small molecules that target mutant p53. However, this is a huge challenge due to the diverse array of expressed p53 mutant proteins [141]. Therefore, p53 is a challenging protein to target for the development of inhibitors. Nonetheless, progress in unraveling the structure of p53 and its interactions with partners has opened the door to the exploration and development of a multitude of molecules that hold promise to reinstate the tumor-suppressing functions of p53 [43].
As indicated by various studies, the observed widespread inactivation of p53 is a prevalent characteristic in NSCLC [142,143,144,145]. This suggests that the restoration of p53’s anticancer function with a p53 activator may represent a hopeful therapeutic strategy for treatment in patients with NSCLC [146,147,148,149]. Some p53 small-molecule activators have been developed and investigated with the aim of restoring the functionality of the p53 protein. Several of these hopeful compounds are currently being subjected to clinical trial evaluation. In this regard, encouraging therapeutic outcomes have been noted in preclinical and clinical studies involving the treatment of solid and hematological tumors with p53 activators specifically designed to disrupt the MDM2/X–p53 interaction [150,151,152].
For example, Kevetrin, (thioureidobutyronitrile or 3-cyanopropyl carbamimidothioate hydrochloride, C5H10ClN3S) is a small-molecule compound displaying activity both dependent on and independent of p53. It has demonstrated favorable tolerability and therapeutic potential across a spectrum of solid tumors, encompassing lung, breast, colon, and ovarian cancers [153,154,155,156].
Furthermore, the development of a synthetic small-molecule p53 activator named NA-17, whose action would be mediated by reorganization of the Bak-Bcl-Xl complex and activation of transcriptional regulation, has shown hopeful results in preclinical models of NSCLC [157]. Nevertheless, in normal cells and in oncogene-driven tumors, this compound has demonstrated relatively high toxicity and limited therapeutic efficacy, respectively. There is potential for obtaining p53 activators with both high efficiency and low toxicity through the optimization of the lead molecule [158]. In their study, they conducted high-performance screening of optimized compounds from NA-17, with the aim of finding new activators of p53. MX-C2 and MX-C3 molecules were discovered, and as noteworthy candidates, both compounds demonstrating substantial therapeutic efficacy in oncogene-driven tumor models. Like NA-17, these compounds were able to induce the activation of p53 by phosphorylating serine-392 without inducing DNA damage. Interestingly, in NSCLC cells and in control cell lines, both molecules exhibited extensive antitumor activity and reduced toxicity, respectively [158].
LUAD stands as the second most common category, comprising 20% to 30% of deaths attributed to lung carcinoma [116,159]. However, unlike LUAD, for which targeted therapies including the anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitors have proven significantly effective [160], there is currently no approved vanguard targeted therapy for the management of individuals diagnosed with LUSC [161,162,163].
In recent times, interventions utilizing immune checkpoint blockades through antibodies that hinder inhibitory immune control proteins, like programmed cell death protein 1 (PD-1) or its ligand (PD-L1), have surfaced as pivotal elements in the established treatment protocol for LUSC patients. However, despite these advancements, the rate of response remains modest. Hence, the identification of potent therapeutics stands as a crucial and pressing unmet requirement for individuals diagnosed with LUSC [164,165]. Targeting of the Notch ligand DLL3 has shown promise in the development of innovative approaches for LUSC, yielding encouraging initial outcomes [106]. For more details on the transcriptional regulation of airway epithelial cell differentiation and the role of Notch, see [166]. Notwithstanding meticulous genomic examination, discerning the oncogenic catalysts in LUSC persists as a formidable challenge [116,120].
Recently, Niu et al. conducted a review on advancements in epigenetic treatments, immune checkpoint inhibitors (ICIs), and diverse combination approaches involving ICIs and additional targeted interventions for LUSC. The review also delved into the potential opportunities and obstacles associated with exploring and implementing innovative therapeutic approaches for LUSC [167]. An initial-phase clinical trial is investigating vaccination of tumor using the TP53-DC vaccine in conjunction with nivolumab and ipilimumab in SCLC. Additional approaches aiming to enhance the immunogenicity of tumor through targeted therapies, including histone deacetylase (HDAC), DNA methyltransferases (DNMTs), or poly-ADP ribose polymerase (PARP) inhibitors, integrated with ICIs, are also undergoing evaluation in initial-phase clinical investigations [106].
TP53 mutations significantly affect the response to standard chemotherapy in lung cancer patients. For example, TP53 mutations confer resistance to platinum-based chemotherapy, taxanes, and etoposide [168,169,170,171,172].
The TP53-associated signature is a specific and independent prognostic biomarker for LUSC patients and could provide potential prognostic biomarker or therapeutic targets for the development of novel immunotherapies and chemotherapies [173].
Several novel targeted therapies are being developed to specifically target TP53-mutated LCs [174]. These therapies focus on reactivating or bypassing the dysfunctional p53 pathway, exploiting synthetic lethality, and combining existing treatments to enhance efficacy, for example, APR-246, PLK4-inhibitors, and mitophagy inhibitors [171,173,175,176]. On the other hand, there are some biomarkers and clinical features that can predict the likelihood of TP53 mutation in LC patients, for instance, KRAS and TP53 co-mutation, TP53 mutations in normal airway epithelium, tumor mutation burden, smoking history, imaging, and radiomics [177,178,179,180,181,182,183,184].
TP53 gene expression in LUSC patients was analyzed with the expression of several genes from cBioPortal datasets. This analysis revealed that the expression of RAP1A and RHOC genes is most closely related to p53 gene expression (Figure 4a and Figure 4b, respectively). Ras-associated protein 1A (Rap1A) and Ras homolog family member C (RhoC) are small GTP-binding proteins categorized within the Ras subfamily. These proteins exhibit a dynamic transition between an inactive GDP-bound state and an active GTP-bound state [185,186]. While Ras and Rap1A share nearly identical effectors in the vicinity of the cell surface, there is a distinction in their activation locations. Rap1A undergoes activation in the perinuclear region, in contrast to most Ras proteins, which undergo activation at the plasma membrane [187]. p53 regulates RhoC transcription and activation [188], and as for Rap1A, it has been proposed that there is a putative binding site of Rap1A to p53 [189]. Both proteins could be promising targets in patients with LUSC.
Mutations in the TP53 gene are common in NSCLC and have significant implications for clinical outcomes. The correlation between p53 mutations and clinical outcomes can vary between the two principal subtypes (LUAD and LUSC) due to differences in their biology and mutation profiles [89,120].
In LUAD, TP53 mutations are generally associated with a worse prognosis. Patients with TP53 mutations tend to have lower overall survival rates compared to those without these mutations. Studies have shown that TP53 mutations in LUAD are linked to higher tumor grade, increased metastasis, and resistance to certain therapies, contributing to poorer outcomes. TP53-mutant LUAD may exhibit resistance to traditional chemotherapies and targeted therapies, making treatment more challenging. The presence of TP53 mutations can influence the effectiveness of emerging treatments such as immunotherapy. Some studies suggest that TP53 mutations might be associated with better responses to ICIs, although this is an area of active research, and findings are not yet conclusive [190,191].
In LUSC, TP53 mutations are also associated with poor clinical outcomes. Similar to LUAD, patients with TP53-mutant LUSC often have a worse prognosis, with lower overall survival rates and higher rates of disease recurrence. The high prevalence of TP53 mutations in LUSC contributes to its aggressive nature and poor response to standard treatments. TP53 mutations in LUSC are linked to resistance to conventional chemotherapy and radiation therapy, contributing to poorer clinical outcomes. As with LUAD, there is ongoing research into the impact of TP53 mutations on the response to immunotherapy in LUSC. Some studies suggest that these mutations might be predictive of a favorable response to ICIs [190,191].
The frequency of TP53 mutations varies significantly across different subtypes of LC. The two major subtypes of NSCLC, LUAD and LUSC, each show distinct patterns of TP53 mutations. Additionally, SCLC, a less common but more aggressive type of LC, also displays a unique pattern of TP53 mutations. TP53 mutations in LUAD often involve missense mutations, particularly in the DBD, which lead to the production of a dysfunctional p53 protein. Other types of mutations, such as nonsense and frameshift mutations, are also present but less common. Similar to LUAD, missense mutations are the most prevalent type of TP53 mutation in LUSC. These mutations typically affect the DBD and result in loss of p53 function. Nonsense and frameshift mutations also affect the DBD. SCLC is characterized by a high frequency of both missense and truncating mutations (nonsense and frameshift), leading to complete loss of p53 function. The mutation pattern in SCLC often involves extensive genomic instability [89,94,120,190,192,193,194].
cBioPortal analysis provides a comprehensive view of TP53 alterations in LC subtypes, revealing their prevalence, types, and functional impacts. These insights help us understand the crucial role of TP53 in lung cancer biology, highlighting the importance of p53 in maintaining genomic stability and suppressing tumor development. Furthermore, the patterns of TP53 mutations observed in cBioPortal data inform our understanding of prognosis and therapeutic responses, offering potential avenues for targeted treatments and personalized medicine approaches in lung cancer [128,130,190,192,193,194,195,196].
Targeting TP53 mutations in LC treatment presents several challenges due to the complex nature of the TP53 gene and its critical role in regulating cell growth and apoptosis. Researchers are actively working to address these challenges through various innovative approaches. Here are the main challenges and strategies being employed. High mutation diversity: TP53 mutations are highly diverse, with hundreds of different mutations identified in various cancers. This diversity makes it difficult to develop a one-size-fits-all treatment [9]. LOF: Many TP53 mutations result in a complete loss of tumor suppressor function, making it challenging to restore normal p53 activity. Resistance mechanism: TP53 mutations can confer resistance to conventional therapies such as chemotherapy and radiation, complicating treatment regimens. Detection and monitoring: Accurately detecting and monitoring TP53 mutations in tumors can be difficult due to the heterogeneous nature of LC and the mutation profile in each case [174,197,198,199,200,201,202].
There are emerging strategies for early detection and prevention of TP53-driven lung cancers, for example, advanced molecular profiling and liquid biopsies. Advanced molecular profiling, including NGS, is crucial for early detection of TP53 mutations in LC. By analyzing tumor DNA from tissue samples, clinicians can identify specific mutations that drive cancer progression. NGS allows for comprehensive genomic profiling, facilitating the identification of TP53 mutations even at early stages of cancer development [203,204]. Liquid biopsies offer a non-invasive alternative for detecting TP53 mutations by analyzing ctDNA in blood samples. This method enables continuous monitoring of mutation status, providing early indications of cancer development or progression without the need for repeated tissue biopsies [10]. Chemoprevention and lifestyle interventions aim to either prevent the occurrence of mutations or mitigate their effects once they occur. For instance, antioxidants and other compounds that reduce oxidative stress may help in reducing mutation rates. Preventive strategies also include lifestyle modifications, particularly smoking cessation. Smoking is a major risk factor for TP53 mutations in lung cancer, and quitting smoking significantly reduces the risk [205,206,207,208,209,210]. Early screening programs are another current strategy. Screening programs targeting high-risk populations, such as long-term smokers and individuals with a family history of lung cancer, are being implemented to detect early signs of TP53 mutations. Also, genetic screening for individuals with a hereditary predisposition to TP53 mutations (e.g., those with Li–Fraumeni syndrome) can help in early detection and preventive measures [211,212,213,214,215,216,217,218,219]. Last but not least are targeted therapies and immunoprevention. These therapies aim to either restore normal p53 function or exploit vulnerabilities in TP53-mutated cells. For example, small molecules that can reactivate mutant p53 proteins or induce synthetic lethality are under investigation [220,221,222,223,224,225]. Immunopreventive strategies involve using vaccines or immune-modulating agents to prevent the development of TP53-driven cancers. By enhancing the immune system’s ability to recognize and eliminate precancerous cells with TP53 mutations, these strategies aim to prevent cancer before it fully develops [226,227,228,229,230,231,232].
Even with recent advances, the molecular basis of lung carcinogenesis needs to be further studied to better understand the molecular pathways involved in lung tumorigenesis. Since p53-related genetic alterations are a common denominator in all cancers, including lung cancer, further study of the molecular alterations of p53 is necessary to understand how this protein exerts its antitumor activity. These studies are of great value for the development of new cancer treatments using highly effective methods directed exclusively against cancer cells. Understanding the role of p53 in LUSC, both in terms of initiation and progression, has potential therapeutic implications. For example, strategies aimed at restoring p53 function or targeting the consequences of p53 mutations could provide avenues for novel LUSC therapies. Furthermore, considering p53 status in the context of personalized medicine approaches could facilitate more effective and individualized therapeutic strategies for LUSC patients.

5. Conclusions

This year is the 45th anniversary of the discovery of one of the most relevant proteins: p53. This phosphoprotein still has much to be studied, especially in elucidating the finer mechanistic details of its involvement in LUSC. It also remains a scientific challenge today to find effective drugs and new therapies in this field that are specifically aimed at counteracting the harmful effects of p53 in lung cancer cells. In the current personalized medicine era, fully comprehending the function of p53 and its variants in the behavior of lung cancer is crucial for shaping the diagnosis and treatment landscape of the disease.

Author Contributions

Conceptualization, D.A.B. and G.C.-L.; methodology, D.A.B. and G.C.-L.; software, D.A.B. and A.R.-G.; validation, D.A.B., G.C.-L., A.R.-G., S.M.-N. and J.M.C.-G.; formal analysis, D.A.B. and G.C.-L.; investigation, D.A.B. and G.C.-L.; resources, D.A.B. and G.C.-L.; data set analysis, A.R.-G., writing—original draft preparation, D.A.B., G.C.-L., S.M.-N. and J.M.C.-G.; writing review and editing, D.A.B., G.C.-L., M.O.-G., N.D.V.-D.P., A.D.-P., A.R.-G., S.M.-N. and J.M.C.-G.; visualization, D.A.B., G.C.-L., M.O.-G., N.D.V.-D.P., A.D.-P., A.R.-G., S.M.-N. and J.M.C.-G.; supervision, S.M.-N. and J.M.C.-G.; project administration, J.M.C.-G.; funding acquisition, J.M.C.-G. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by BFU2017-85547-P, TED2021-130560B-I00, and PID2021-126905NB-I00 grants from the Ministry of Economy, IB18014 from Junta de Extremadura to J.M.C.-G., and GR21140 from Junta de Extremadura to S.M.-N. All Spanish funding is co-sponsored by the European Union FEDER program.

Conflicts of Interest

The authors declare no conflicts of interest.

Acronyms

AKTProtein kinase BLUSCLung squamous cell carcinoma
ALKAnaplastic lymphoma kinaseMAPKMitogen-activated protein kinase
AMPKAMP-activated protein kinaseMDM2Mouse double minute 2 homolog
AT1Alveolar type 1MDMXMouse double minute X
AT2Alveolar type 2 mRNAMessenger RNA
ATMAtaxia telangiectasia mutatedmTORMammalian target of rapamycin
ATRAtaxia telangiectasia and Rad3-related proteinNGSNext-generation sequencing
CDKN2ACyclin-dependent kinase inhibitor 2ANSCLCNon-small-cell lung cancer
CTDC-terminal domainODOligomerization domain
ctDNACirculating tumor DNAp53REp53-response elements
DBDDNA-binding domainPARPPoly-ADP ribose polymerase
DLL3Delta-like ligand 3PD-1 Programmed cell death protein 1
DNADeoxyribonucleic acidPD-L1 Programmed cell death 1 ligand 1
DNMTDNA methyltransferasePI3KPhosphatidylinositol 3-kinase
EGFREpidermal growth factor receptorPRDProline-rich domain
FLp53Full-length p53PTENPhosphatase and tensin homolog
GOFGain of functionRap1ARas-associated protein 1A
HDACHistone deacetylaseRb1Retinoblastoma 1 protein
ICIsImmune checkpoint inhibitorsRhoCRas homolog family member C
JNKc-Jun N-terminal kinaseSCLCSmall-cell lung cancer
LCLung cancerTADTransactivation domain
LOFLoss of functionYAPYes-associated protein
LUADLung adenocarcinoma

References

  1. Vogelstein, B.; Lane, D.; Levine, A.J. Surfing the P53 Network. Nature 2000, 408, 307–310. [Google Scholar] [CrossRef] [PubMed]
  2. Aylon, Y.; Oren, M. The Paradox of P53: What, How, and Why? Cold Spring Harb. Perspect. Med. 2016, 6, a026328. [Google Scholar] [CrossRef] [PubMed]
  3. Dejosez, M.; Ura, H.; Brandt, V.L.; Zwaka, T.P. Safeguards for Cell Cooperation in Mouse Embryogenesis Shown by Genome-Wide Cheater Screen. Science 2013, 341, 1511–1514. [Google Scholar] [CrossRef] [PubMed]
  4. Vousden, K.H.; Prives, C. Blinded by the Light: The Growing Complexity of P53. Cell 2009, 137, 413–431. [Google Scholar] [CrossRef] [PubMed]
  5. Kenzelmann Broz, D.; Mello, S.S.; Bieging, K.T.; Jiang, D.; Dusek, R.L.; Brady, C.A.; Sidow, A.; Attardi, L.D. Global Genomic Profiling Reveals an Extensive P53-Regulated Autophagy Program Contributing to Key P53 Responses. Genes Dev. 2013, 27, 1016–1031. [Google Scholar] [CrossRef] [PubMed]
  6. Skoulidis, F.; Heymach, J.V. Co-Occurring Genomic Alterations in Non-Small-Cell Lung Cancer Biology and Therapy. Nat. Rev. Cancer 2019, 19, 495–509. [Google Scholar] [CrossRef] [PubMed]
  7. Levine, A.J.; Oren, M. The First 30 Years of P53: Growing Ever More Complex. Nat. Rev. Cancer 2009, 9, 749–758. [Google Scholar] [CrossRef]
  8. Tuval, A.; Strandgren, C.; Heldin, A.; Palomar-Siles, M.; Wiman, K.G. Pharmacological Reactivation of P53 in the Era of Precision Anticancer Medicine. Nat. Rev. Clin. Oncol. 2024, 21, 106–120. [Google Scholar] [CrossRef] [PubMed]
  9. Cai, X.; Sheng, J.; Tang, C.; Nandakumar, V.; Ye, H.; Ji, H.; Tang, H.; Qin, Y.; Guan, H.; Lou, F.; et al. Frequent Mutations in EGFR, KRAS and TP53 Genes in Human Lung Cancer Tumors Detected by Ion Torrent DNA Sequencing. PLoS ONE 2014, 9, e95228. [Google Scholar] [CrossRef]
  10. Christopoulos, P.; Dietz, S.; Kirchner, M.; Volckmar, A.L.; Endris, V.; Neumann, O.; Ogrodnik, S.; Heussel, C.P.; Herth, F.J.; Eichhorn, M.; et al. Detection of TP53 Mutations in Tissue or Liquid Rebiopsies at Progression Identifies ALK+ Lung Cancer Patients with Poor Survival. Cancers 2019, 11, 124. [Google Scholar] [CrossRef]
  11. Papavassiliou, K.A.; Sofianidi, A.A.; Gogou, V.A.; Anagnostopoulos, N.; Papavassiliou, A.G. P53 and Rb Aberrations in Small Cell Lung Cancer (SCLC): From Molecular Mechanisms to Therapeutic Modulation. Int. J. Mol. Sci. 2024, 25, 2479. [Google Scholar] [CrossRef] [PubMed]
  12. Burkhart, D.L.; Sage, J. Cellular Mechanisms of Tumour Suppression by the Retinoblastoma Gene. Nat. Rev. Cancer 2008, 8, 671–682. [Google Scholar] [CrossRef]
  13. Song, M.S.; Salmena, L.; Pandolfi, P.P. The Functions and Regulation of the PTEN Tumour Suppressor. Nat. Rev. Mol. Cell Biol. 2012, 13, 283–296. [Google Scholar] [CrossRef] [PubMed]
  14. Iwakawa, R.; Kohno, T.; Totoki, Y.; Shibata, T.; Tsuchihara, K.; Mimaki, S.; Tsuta, K.; Narita, Y.; Nishikawa, R.; Noguchi, M.; et al. Expression and Clinical Significance of Genes Frequently Mutated in Small Cell Lung Cancers Defined by Whole Exome/RNA Sequencing. Carcinogenesis 2015, 36, 616–621. [Google Scholar] [CrossRef] [PubMed]
  15. Velez, M.G.; Kosiorek, H.E.; Egan, J.B.; McNatty, A.L.; Riaz, I.B.; Hwang, S.R.; Stewart, G.A.; Ho, T.H.; Moore, C.N.; Singh, P.; et al. Differential Impact of Tumor Suppressor Gene (TP53, PTEN, RB1) Alterations and Treatment Outcomes in Metastatic, Hormone-Sensitive Prostate Cancer. Prostate Cancer Prostatic Dis. 2022, 25, 479–483. [Google Scholar] [CrossRef] [PubMed]
  16. Zhang, L.; Liu, C.; Zhang, B.; Zheng, J.; Singh, P.K.; Bshara, W.; Wang, J.; Gomez, E.C.; Zhang, X.; Wang, Y.; et al. PTEN Loss Expands the Histopathologic Diversity and Lineage Plasticity of Lung Cancers Initiated by Rb1/Trp53 Deletion. J. Thorac. Oncol. 2023, 18, 324–338. [Google Scholar] [CrossRef] [PubMed]
  17. Joruiz, S.M.; Bourdon, J.C. P53 Isoforms: Key Regulators of the Cell Fate Decision. Cold Spring Harb. Perspect. Med. 2016, 6, a026039. [Google Scholar] [CrossRef] [PubMed]
  18. Lane, D.P.; Cheok, C.F.; Brown, C.; Madhumalar, A.; Ghadessy, F.J.; Verma, C. Mdm2 and P53 Are Highly Conserved from Placozoans to Man. Cell Cycle 2010, 9, 540–547. [Google Scholar] [CrossRef] [PubMed]
  19. Dumont, P.; Leu, J.I.J.; Della Pietra, A.C.; George, D.L.; Murphy, M. The Codon 72 Polymorphic Variants of P53 Have Markedly Different Apoptotic Potential. Nat. Genet 2003, 33, 357–365. [Google Scholar] [CrossRef]
  20. Garritano, S.; Gemignani, F.; Palmero, E.I.; Olivier, M.; Martel-Planche, G.; Le Calvez-Kelm, F.; Brugiéres, L.; Vargas, F.R.; Brentani, R.R.; Ashton-Prolla, P.; et al. Detailed Haplotype Analysis at the TP53 Locus in p.R337H Mutation Carriers in the Population of Southern Brazil: Evidence for a Founder Effect. Hum. Mutat. 2010, 31, 143–150. [Google Scholar] [CrossRef]
  21. Wu, D.; Zhang, Z.; Chu, H.; Xu, M.; Xue, Y.; Zhu, H.; Zhang, Z. Intron 3 Sixteen Base Pairs Duplication Polymorphism of P53 Contributes to Breast Cancer Susceptibility: Evidence from Meta-Analysis. PLoS ONE 2013, 8, e61662. [Google Scholar] [CrossRef]
  22. Amendolare, A.; Marzano, F.; Petruzzella, V.; Vacca, R.A.; Guerrini, L.; Pesole, G.; Sbisà, E.; Tullo, A. The Underestimated Role of the P53 Pathway in Renal Cancer. Cancers 2022, 14, 5733. [Google Scholar] [CrossRef]
  23. Bykov, V.J.N.; Eriksson, S.E.; Bianchi, J.; Wiman, K.G. Targeting Mutant P53 for Efficient Cancer Therapy. Nat. Rev. Cancer 2018, 18, 89–102. [Google Scholar] [CrossRef]
  24. Choudhary, H.B.; Mandlik, S.K.; Mandlik, D.S. Role of P53 Suppression in the Pathogenesis of Hepatocellular Carcinoma. World J. Gastrointest. Pathophysiol. 2023, 14, 46–70. [Google Scholar] [CrossRef]
  25. Donehower, L.A.; Soussi, T.; Korkut, A.; Liu, Y.; Schultz, A.; Cardenas, M.; Li, X.; Babur, O.; Hsu, T.K.; Lichtarge, O.; et al. Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas. Cell Rep. 2019, 28, 1370–1384.e5. [Google Scholar] [CrossRef]
  26. Feng, H.; Xu, H.; Shi, X.; Ding, G.; Yan, C.; Li, L.; Jian, Z.; Yang, X.; Guo, H.; Li, F.; et al. TP53 Exon 5 Mutation Indicates Poor Progression-Free Survival for Patients with Stage IV NSCLC. Front. Biosci. 2023, 28, 147. [Google Scholar] [CrossRef]
  27. Guo, X.; Dong, L.; Liu, H.; Chen, X. TP53, NOTCH2, and STK11 Mutations in a Rare Tumor of Non-Small Cell Lung Carcinoma with Diffuse Coexpression of TTF1 and P40 in the Same Tumor Cells. Int. J. Surg. Pathol. 2023, 31, 1041–1047. [Google Scholar] [CrossRef]
  28. Kim, M.P.; Lozano, G. Mutant P53 Partners in Crime. Cell Death Differ. 2018, 25, 161–168. [Google Scholar] [CrossRef]
  29. Marei, H.E.; Althani, A.; Afifi, N.; Hasan, A.; Caceci, T.; Pozzoli, G.; Morrione, A.; Giordano, A.; Cenciarelli, C. P53 Signaling in Cancer Progression and Therapy. Cancer Cell Int. 2021, 21, 703. [Google Scholar] [CrossRef]
  30. Dolgin, E. The Most Popular Genes in the Human Genome. Nature 2017, 551, 427–431. [Google Scholar] [CrossRef]
  31. Bourdon, J.C.; Fernandes, K.; Murray-Zmijewski, F.; Liu, G.; Diot, A.; Xirodimas, D.P.; Saville, M.K.; Lane, D.P. P53 Isoforms Can Regulate P53 Transcriptional Activity. Genes Dev. 2005, 19, 2122–2137. [Google Scholar] [CrossRef]
  32. Marcel, V.; Perrier, S.; Aoubala, M.; Ageorges, S.; Groves, M.J.; Diot, A.; Fernandes, K.; Tauro, S.; Bourdon, J.C. Δ160p53 Is a Novel N-Terminal P53 Isoform Encoded by Δ133p53 Transcript. FEBS Lett. 2010, 584, 4463–4468. [Google Scholar] [CrossRef]
  33. Reinhardt, L.S.; Zhang, X.; Wawruszak, A.; Groen, K.; De Iuliis, G.N.; Avery-Kiejda, K.A. Good Cop, Bad Cop: Defining the Roles of Δ40p53 in Cancer and Aging. Cancers 2020, 12, 1659. [Google Scholar] [CrossRef]
  34. Candeias, M.M.; Powell, D.J.; Roubalova, E.; Apcher, S.; Bourougaa, K.; Vojtesek, B.; Bruzzoni-Giovanelli, H.; Fåhraeus, R. Expression of P53 and P53/47 Are Controlled by Alternative Mechanisms of Messenger RNA Translation Initiation. Oncogene 2006, 25, 6936–6947. [Google Scholar] [CrossRef]
  35. Ray, P.S.; Grover, R.; Das, S. Two Internal Ribosome Entry Sites Mediate the Translation of P53 Isoforms. EMBO Rep. 2006, 7, 404–410. [Google Scholar] [CrossRef]
  36. Solomon, H.; Bräuning, B.; Fainer, I.; Ben-Nissan, G.; Rabani, S.; Goldfinger, N.; Moscovitz, O.; Shakked, Z.; Rotter, V.; Sharon, M. Post-Translational Regulation of P53 Function through 20S Proteasome-Mediated Cleavage. Cell Death Differ. 2017, 24, 2187–2198. [Google Scholar] [CrossRef]
  37. Vousden, K.H.; Lane, D.P. P53 in Health and Disease. Nat. Rev. Mol. Cell Biol. 2007, 8, 275–283. [Google Scholar] [CrossRef]
  38. Momand, J.; Wu, H.H.; Dasgupta, G. MDM2--Master Regulator of the P53 Tumor Suppressor Protein. Gene 2000, 242, 15–29. [Google Scholar] [CrossRef]
  39. Michael, D.; Oren, M. The P53-Mdm2 Module and the Ubiquitin System. Semin. Cancer Biol. 2003, 13, 49–58. [Google Scholar] [CrossRef] [PubMed]
  40. Michael, D.; Oren, M. The P53 and Mdm2 Families in Cancer. Curr. Opin. Genet. Dev. 2002, 12, 53–59. [Google Scholar] [CrossRef] [PubMed]
  41. Pitolli, C.; Wang, Y.; Mancini, M.; Shi, Y.; Melino, G.; Amelio, I. Do Mutations Turn P53 into an Oncogene? Int. J. Mol. Sci. 2019, 20, 6241. [Google Scholar] [CrossRef] [PubMed]
  42. Haupt, Y.; Maya, R.; Kazaz, A.; Oren, M. Mdm2 Promotes the Rapid Degradation of P53. Nature 1997, 387, 296–299. [Google Scholar] [CrossRef]
  43. Marvalim, C.; Datta, A.; Lee, S.C. Role of P53 in Breast Cancer Progression: An Insight into P53 Targeted Therapy. Theranostics 2023, 13, 1421–1442. [Google Scholar] [CrossRef]
  44. Bargonetti, J.; Prives, C. Gain-of-Function Mutant P53: History and Speculation. J. Mol. Cell Biol. 2019, 11, 605–609. [Google Scholar] [CrossRef]
  45. Ingallina, E.; Sorrentino, G.; Bertolio, R.; Lisek, K.; Zannini, A.; Azzolin, L.; Severino, L.U.; Scaini, D.; Mano, M.; Mantovani, F.; et al. Mechanical Cues Control Mutant P53 Stability through a Mevalonate-RhoA Axis. Nat. Cell Biol. 2018, 20, 28–35. [Google Scholar] [CrossRef]
  46. Liao, P.; Zeng, S.X.; Zhou, X.; Chen, T.; Zhou, F.; Cao, B.; Jung, J.H.; Del Sal, G.; Luo, S.; Lu, H. Mutant P53 Gains Its Function via C-Myc Activation upon CDK4 Phosphorylation at Serine 249 and Consequent PIN1 Binding. Mol. Cell 2017, 68, 1134–1146.e6. [Google Scholar] [CrossRef]
  47. Mukherjee, S.; Maddalena, M.; Lu, Y.Q.; Martinez, S.; Nataraj, N.B.; Noronha, A.; Sinha, S.; Teng, K.; Cohen-Kaplan, V.; Ziv, T.; et al. Cross-Talk between Mutant P53 and P62/SQSTM1 Augments Cancer Cell Migration by Promoting the Degradation of Cell Adhesion Proteins. Proc. Natl. Acad. Sci. USA 2022, 119, e2119644119. [Google Scholar] [CrossRef]
  48. Parrales, A.; Ranjan, A.; Iyer, S.V.; Padhye, S.; Weir, S.J.; Roy, A.; Iwakuma, T. DNAJA1 Controls the Fate of Misfolded Mutant P53 through the Mevalonate Pathway. Nat. Cell Biol. 2016, 18, 1233–1243. [Google Scholar] [CrossRef]
  49. Pilley, S.; Rodriguez, T.A.; Vousden, K.H. Mutant P53 in Cell-Cell Interactions. Genes Dev. 2021, 35, 433–448. [Google Scholar] [CrossRef]
  50. Redman-Rivera, L.N.; Shaver, T.M.; Jin, H.; Marshall, C.B.; Schafer, J.M.; Sheng, Q.; Hongo, R.A.; Beckermann, K.E.; Wheeler, F.C.; Lehmann, B.D.; et al. Acquisition of Aneuploidy Drives Mutant P53-Associated Gain-of-Function Phenotypes. Nat. Commun. 2021, 12, 5184. [Google Scholar] [CrossRef]
  51. Vaughan, C.A.; Singh, S.; Subler, M.A.; Windle, J.J.; Inoue, K.; Fry, E.A.; Pillappa, R.; Grossman, S.R.; Windle, B.; Andrew Yeudall, W.; et al. The Oncogenicity of Tumor-Derived Mutant P53 Is Enhanced by the Recruitment of PLK3. Nat. Commun. 2021, 12, 704. [Google Scholar] [CrossRef]
  52. Blagih, J.; Zani, F.; Chakravarty, P.; Hennequart, M.; Pilley, S.; Hobor, S.; Hock, A.K.; Walton, J.B.; Morton, J.P.; Gronroos, E.; et al. Cancer-Specific Loss of P53 Leads to a Modulation of Myeloid and T Cell Responses. Cell Rep. 2020, 30, 481–496.e6. [Google Scholar] [CrossRef] [PubMed]
  53. Cui, Y.; Guo, G. Immunomodulatory Function of the Tumor Suppressor P53 in Host Immune Response and the Tumor Microenvironment. Int. J. Mol. Sci. 2016, 17, 1942. [Google Scholar] [CrossRef] [PubMed]
  54. Hassin, O.; Nataraj, N.B.; Shreberk-Shaked, M.; Aylon, Y.; Yaeger, R.; Fontemaggi, G.; Mukherjee, S.; Maddalena, M.; Avioz, A.; Iancu, O.; et al. Different Hotspot P53 Mutants Exert Distinct Phenotypes and Predict Outcome of Colorectal Cancer Patients. Nat. Commun. 2022, 13, 2800. [Google Scholar] [CrossRef] [PubMed]
  55. Jin, S.; Levine, A.J. The P53 Functional Circuit. J. Cell Sci. 2001, 114, 4139–4140. [Google Scholar] [CrossRef] [PubMed]
  56. Levine, A.J. P53, the Cellular Gatekeeper for Growth and Division. Cell 1997, 88, 323–331. [Google Scholar] [CrossRef] [PubMed]
  57. Kogan, S.; Carpizo, D.R. Zinc Metallochaperones as Mutant P53 Reactivators: A New Paradigm in Cancer Therapeutics. Cancers 2018, 10, 166. [Google Scholar] [CrossRef] [PubMed]
  58. Avery-Kiejda, K.A.; Xu, D.Z.; Adams, L.J.; Scott, R.J.; Vojtesek, B.; Lane, D.P.; Hersey, P. Small Molecular Weight Variants of P53 Are Expressed in Human Melanoma Cells and Are Induced by the DNA-Damaging Agent Cisplatin. Clin. Cancer Res. 2008, 14, 1659–1668. [Google Scholar] [CrossRef] [PubMed]
  59. Anensen, N.; Oyan, A.M.; Bourdon, J.C.; Kalland, K.H.; Bruserud, O.; Gjertsen, B.T. A Distinct P53 Protein Isoform Signature Reflects the Onset of Induction Chemotherapy for Acute Myeloid Leukemia. Clin. Cancer Res. 2006, 12, 3985–3992. [Google Scholar] [CrossRef]
  60. Bourdon, J.C.; Khoury, M.P.; Diot, A.; Baker, L.; Fernandes, K.; Aoubala, M.; Quinlan, P.; Purdie, C.A.; Jordan, L.B.; Prats, A.C.; et al. P53 Mutant Breast Cancer Patients Expressing P53γ Have as Good a Prognosis as Wild-Type P53 Breast Cancer Patients. Breast Cancer Res. 2011, 13, R7. [Google Scholar] [CrossRef]
  61. Dos Santos, N.M.; De Oliveira, G.A.P.; Rocha, M.R.; Pedrote, M.M.; Da Silva Ferretti, G.D.; Rangel, L.P.; Morgado-Diaz, J.A.; Silva, J.L.; Gimba, E.R.P. Loss of the P53 Transactivation Domain Results in High Amyloid Aggregation of the Δ40p53 Isoform in Endometrial Carcinoma Cells. J. Biol. Chem. 2019, 294, 9430–9439. [Google Scholar] [CrossRef]
  62. Hofstetter, G.; Berger, A.; Fiegl, H.; Slade, N.; Zori, A.; Holzer, B.; Schuster, E.; Mobus, V.J.; Reimer, D.; Daxenbichler, G.; et al. Alternative Splicing of P53 and P73: The Novel P53 Splice Variant P53delta Is an Independent Prognostic Marker in Ovarian Cancer. Oncogene 2010, 29, 1997–2004. [Google Scholar] [CrossRef] [PubMed]
  63. Oh, L.; Hainaut, P.; Blanchet, S.; Ariffin, H. Expression of P53 N-Terminal Isoforms in B-Cell Precursor Acute Lymphoblastic Leukemia and Its Correlation with Clinicopathological Profiles. BMC Cancer 2020, 20, 110. [Google Scholar] [CrossRef] [PubMed]
  64. Takahashi, R.; Giannini, C.; Sarkaria, J.N.; Schroeder, M.; Rogers, J.; Mastroeni, D.; Scrable, H. P53 Isoform Profiling in Glioblastoma and Injured Brain. Oncogene 2012, 32, 3165–3174. [Google Scholar] [CrossRef]
  65. Hofstetter, G.; Berger, A.; Berger, R.; Zorić, A.; Braicu, E.I.; Reimer, D.; Fiegl, H.; Marth, C.; Zeimet, A.G.; Ulmer, H.; et al. The N-Terminally Truncated P53 Isoform Δ40p53 Influences Prognosis in Mucinous Ovarian Cancer. Int. J. Gynecol. Cancer 2012, 22, 372–379. [Google Scholar] [CrossRef] [PubMed]
  66. Alexandrova, E.M.; Yallowitz, A.R.; Li, D.; Xu, S.; Schulz, R.; Proia, D.A.; Lozano, G.; Dobbelstein, M.; Moll, U.M. Improving Survival by Exploiting Tumour Dependence on Stabilized Mutant P53 for Treatment. Nature 2015, 523, 352–356. [Google Scholar] [CrossRef]
  67. Levine, A.J. Targeting the P53 Protein for Cancer Therapies: The Translational Impact of P53 Research. Cancer Res. 2022, 82, 362–364. [Google Scholar] [CrossRef]
  68. Sabapathy, K.; Lane, D.P. Therapeutic Targeting of P53: All Mutants Are Equal, but Some Mutants Are More Equal than Others. Nat. Rev. Clin. Oncol. 2018, 15, 13–30. [Google Scholar] [CrossRef]
  69. Liu, J.; Zhang, C.; Xu, D.; Zhang, T.; Chang, C.Y.; Wang, J.; Liu, J.; Zhang, L.; Haffty, B.G.; Zong, W.X.; et al. The Ubiquitin Ligase TRIM21 Regulates Mutant P53 Accumulation and Gain of Function in Cancer. J. Clin. Investig. 2023, 133, 1–17. [Google Scholar] [CrossRef] [PubMed]
  70. Efeyan, A.; Serrano, M. P53: Guardian of the Genome and Policeman of the Oncogenes. Cell Cycle 2007, 6, 1006–1010. [Google Scholar] [CrossRef]
  71. Whibley, C.; Pharoah, P.D.P.; Hollstein, M. P53 Polymorphisms: Cancer Implications. Nat. Rev. Cancer 2009, 9, 95–107. [Google Scholar] [CrossRef]
  72. Barnoud, T.; Parris, J.L.D.; Murphy, M.E. Common Genetic Variants in the TP53 Pathway and Their Impact on Cancer. J. Mol. Cell Biol. 2019, 11, 578–585. [Google Scholar] [CrossRef]
  73. Liu, H.; Li, K.; Xia, J.; Zhu, J.; Cheng, Y.; Zhang, X.; Ye, H.; Wang, P. Prediction of Esophageal Cancer Risk Based on Genetic Variants and Environmental Risk Factors in Chinese Population. BMC Cancer 2024, 24, 598. [Google Scholar] [CrossRef]
  74. Shao, Y.; Tan, W.; Zhang, S. P53 Gene Codon 72 Polymorphism and Risk of Esophageal Squamous Cell Carcinoma: A Case/Control Study in a Chinese Population. Dis. Esophagus 2008, 21, 139–143. [Google Scholar] [CrossRef] [PubMed]
  75. Zhang, A.; Shi, T.Y.; Zhao, Y.; Xiang, J.; Yu, D.; Liang, Z.; Xu, C.; Zhang, Q.; Hu, Y.; Wang, D.; et al. No Association between TP53 Arg72Pro Polymorphism and Ovarian Cancer Risk: Evidence from 10113 Subjects. Oncotarget 2017, 8, 112761. [Google Scholar] [CrossRef] [PubMed]
  76. Grochola, L.F.; Zeron-Medina, J.; Mériaux, S.; Bond, G.L. Single-Nucleotide Polymorphisms in the P53 Signaling Pathway. Cold Spring Harb. Perspect. Biol. 2010, 2, a001032. [Google Scholar] [CrossRef]
  77. Lin, Y.M.; Shao, J.; Yin, X.H.; Huang, C.C.; Jia, X.W.; Yuan, Y.D.; Wu, C.J.; Zhen, E.M.; Yao, Z.X.; Zeng, X.T.; et al. Meta-Analysis Results on the Association Between TP53 Codon 72 Polymorphism with the Susceptibility to Oral Cancer. Front. Physiol. 2018, 9, 1014. [Google Scholar] [CrossRef]
  78. Pim, D.; Banks, L. P53 Polymorphic Variants at Codon 72 Exert Different Effects on Cell Cycle Progression. Int. J. Cancer 2004, 108, 196–199. [Google Scholar] [CrossRef] [PubMed]
  79. Hoyos, D.; Greenbaum, B.; Levine, A.J. The Genotypes and Phenotypes of Missense Mutations in the Proline Domain of the P53 Protein. Cell Death Differ. 2022, 29, 938–945. [Google Scholar] [CrossRef] [PubMed]
  80. Hrstka, R.; Coates, P.J.; Vojtesek, B. Polymorphisms in P53 and the P53 Pathway: Roles in Cancer Susceptibility and Response to Treatment. J. Cell Mol. Med. 2009, 13, 440–453. [Google Scholar] [CrossRef]
  81. Wang, Z.; Strasser, A.; Kelly, G.L. Should Mutant TP53 Be Targeted for Cancer Therapy? Cell Death Differ. 2022, 29, 911–920. [Google Scholar] [CrossRef]
  82. Mansur, M.B.; Greaves, M. Convergent TP53 Loss and Evolvability in Cancer. BMC Ecol. Evol. 2023, 23, 54. [Google Scholar] [CrossRef]
  83. Joerger, A.C.; Fersht, A.R. Structural Biology of the Tumor Suppressor P53 and Cancer-Associated Mutants. Adv. Cancer Res. 2007, 97, 1–23. [Google Scholar] [CrossRef] [PubMed]
  84. Corazzari, M.; Collavin, L. Wild-Type and Mutant P53 in Cancer-Related Ferroptosis. A Matter of Stress Management? Front. Genet. 2023, 14, 1148192. [Google Scholar] [CrossRef] [PubMed]
  85. Wang, H.; Guo, M.; Wei, H.; Chen, Y. Targeting P53 Pathways: Mechanisms, Structures, and Advances in Therapy. Signal Transduct. Target. Ther. 2023, 8, 92. [Google Scholar] [CrossRef] [PubMed]
  86. Hollstein, M.; Shomer, B.; Greenblatt, M.; Soussi, T.; Hovig, E.; Montesano, R.; Harris, C.C. Somatic Point Mutations in the P53 Gene of Human Tumors and Cell Lines: Updated Compilation. Nucleic Acids Res. 1996, 24, 137–140. [Google Scholar] [CrossRef] [PubMed]
  87. Joerger, A.C.; Fersht, A.R. Structural Biology of the Tumor Suppressor P53. Annu. Rev. Biochem. 2008, 77, 557–582. [Google Scholar] [CrossRef] [PubMed]
  88. Mogi, A.; Kuwano, H. TP53 Mutations in Nonsmall Cell Lung Cancer. J. Biomed. Biotechnol. 2011, 2011, 583929. [Google Scholar] [CrossRef]
  89. The Cancer Genome Atlas Research Network. Comprehensive Molecular Profiling of Lung Adenocarcinoma. Nature 2014, 511, 543–550, Correction in Nature 2014, 511, 262. [Google Scholar] [CrossRef]
  90. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
  91. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer Statistics, 2022. CA Cancer J. Clin. 2022, 72, 7–33. [Google Scholar] [CrossRef]
  92. Torre, L.A.; Siegel, R.L.; Jemal, A. Lung Cancer Statistics. Adv. Exp. Med. Biol. 2016, 893, 1–19. [Google Scholar] [CrossRef] [PubMed]
  93. Gridelli, C.; Rossi, A.; Carbone, D.P.; Guarize, J.; Karachaliou, N.; Mok, T.; Petrella, F.; Spaggiari, L.; Rosell, R. Non-Small-Cell Lung Cancer. Nat. Rev. Dis. Primers 2015, 1, 15009. [Google Scholar] [CrossRef] [PubMed]
  94. Pikor, L.A.; Ramnarine, V.R.; Lam, S.; Lam, W.L. Genetic Alterations Defining NSCLC Subtypes and Their Therapeutic Implications. Lung Cancer 2013, 82, 179–189. [Google Scholar] [CrossRef] [PubMed]
  95. Lv, D.; Xu, C.; Wang, C.; Sang, Q. Lung Squamous Cell Carcinoma with EML4-ALK Fusion and TP53 Co-Mutation Treated with Ensartinib: A Case Report and Literature Review. Zhongguo Fei Ai Za Zhi 2023, 26, 78–82. [Google Scholar] [CrossRef]
  96. Muller, P.A.J.; Vousden, K.H. P53 Mutations in Cancer. Nat. Cell Biol. 2013, 15, 2–8. [Google Scholar] [CrossRef] [PubMed]
  97. Olivier, M.; Hollstein, M.; Hainaut, P. TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use. Cold Spring Harb. Perspect. Biol. 2010, 2, a001008. [Google Scholar] [CrossRef]
  98. Rivlin, N.; Brosh, R.; Oren, M.; Rotter, V. Mutations in the P53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis. Genes Cancer 2011, 2, 466–474. [Google Scholar] [CrossRef] [PubMed]
  99. Muller, P.A.J.; Vousden, K.H. Mutant P53 in Cancer: New Functions and Therapeutic Opportunities. Cancer Cell 2014, 25, 304–317. [Google Scholar] [CrossRef] [PubMed]
  100. Poeta, M.L.; Manola, J.; Goldwasser, M.A.; Forastiere, A.; Benoit, N.; Califano, J.A.; Ridge, J.A.; Goodwin, J.; Kenady, D.; Saunders, J.; et al. TP53 Mutations and Survival in Squamous-Cell Carcinoma of the Head and Neck. N. Engl. J. Med. 2007, 357, 2552–2561. [Google Scholar] [CrossRef]
  101. Adorno, M.; Cordenonsi, M.; Montagner, M.; Dupont, S.; Wong, C.; Hann, B.; Solari, A.; Bobisse, S.; Rondina, M.B.; Guzzardo, V.; et al. A Mutant-P53/Smad Complex Opposes P63 to Empower TGFbeta-Induced Metastasis. Cell 2009, 137, 87–98. [Google Scholar] [CrossRef]
  102. Malkin, D. Li-Fraumeni Syndrome. Genes Cancer 2011, 2, 475–484. [Google Scholar] [CrossRef] [PubMed]
  103. Cooks, T.; Pateras, I.S.; Jenkins, L.M.; Patel, K.M.; Robles, A.I.; Morris, J.; Forshew, T.; Appella, E.; Gorgoulis, V.G.; Harris, C.C. Mutant P53 Cancers Reprogram Macrophages to Tumor Supporting Macrophages via Exosomal MiR-1246. Nat. Commun. 2018, 9, 771. [Google Scholar] [CrossRef] [PubMed]
  104. Garrido-Jimenez, S.; Barrera-Lopez, J.F.; Diaz-Chamorro, S.; Mateos-Quiros, C.M.; Rodriguez-Blanco, I.; Marquez-Perez, F.L.; Lorenzo, M.J.; Centeno, F.; Roman, A.C.; Carvajal-Gonzalez, J.M. P53 Regulation by MDM2 Contributes to Self-Renewal and Differentiation of Basal Stem Cells in Mouse and Human Airway Epithelium. FASEB J. 2021, 35, e21816. [Google Scholar] [CrossRef] [PubMed]
  105. Kaiser, A.M.; Gatto, A.; Hanson, K.J.; Zhao, R.L.; Raj, N.; Ozawa, M.G.; Seoane, J.A.; Bieging-Rolett, K.T.; Wang, M.; Li, I.; et al. P53 Governs an AT1 Differentiation Programme in Lung Cancer Suppression. Nature 2023, 619, 851–859. [Google Scholar] [CrossRef] [PubMed]
  106. Salehi-Rad, R.; Li, R.; Paul, M.K.; Dubinett, S.M.; Liu, B. The Biology of Lung Cancer: Development of More Effective Methods for Prevention, Diagnosis, and Treatment. Clin. Chest. Med. 2020, 41, 25–38. [Google Scholar] [CrossRef]
  107. Gu, J.; Zhou, Y.; Huang, L.; Ou, W.; Wu, J.; Li, S.; Xu, J.; Feng, J.; Liu, B. TP53 Mutation Is Associated with a Poor Clinical Outcome for Non-Small Cell Lung Cancer: Evidence from a Meta-Analysis. Mol. Clin. Oncol. 2016, 5, 705–713. [Google Scholar] [CrossRef]
  108. Jiao, X.D.; Qin, B.D.; You, P.; Cai, J.; Zang, Y.S. The Prognostic Value of TP53 and Its Correlation with EGFR Mutation in Advanced Non-Small Cell Lung Cancer, an Analysis Based on CBioPortal Data Base. Lung Cancer 2018, 123, 70–75. [Google Scholar] [CrossRef] [PubMed]
  109. Wang, Y.; Wang, Z.; Piha-Paul, S.; Janku, F.; Subbiah, V.; Shi, N.; Hess, K.; Broaddus, R.; Shan, B.; Naing, A.; et al. Outcome Analysis of Phase I Trial Patients with Metastatic KRAS and/or TP53 Mutant Non-Small Cell Lung Cancer. Oncotarget 2018, 9, 33258–33270. [Google Scholar] [CrossRef]
  110. Fregni, M.; Ciribilli, Y.; Zawacka-Pankau, J.E. The Therapeutic Potential of the Restoration of the P53 Protein Family Members in the EGFR-Mutated Lung Cancer. Int. J. Mol. Sci. 2022, 23, 7213. [Google Scholar] [CrossRef]
  111. Sun, J.; Wang, X.; Liu, W.; Ji, P.; Shang, A.; Wu, J.; Zhou, H.; Quan, W.; Yao, Y.; Yang, Y.; et al. Novel Evidence for Retinoic Acid-Induced G (Rig-G) as a Tumor Suppressor by Activating P53 Signaling Pathway in Lung Cancer. FASEB J. 2020, 34, 11900–11912. [Google Scholar] [CrossRef]
  112. Jin, K.R.; Yun, J.C.; Ryoo, B.Y.; Im, I.N.; Sung, H.Y.; Cheol, H.K.; Jae, C.L. P53 Enhances Gefitinib-Induced Growth Inhibition and Apoptosis by Regulation of Fas in Non-Small Cell Lung Cancer. Cancer Res. 2007, 67, 1163–1169. [Google Scholar] [CrossRef]
  113. Lee, J.S.; Yoon, A.; Kalapurakal, S.K.; Ro, J.Y.; Lee, J.J.; Tu, N.; Hittelman, W.N.; Hong, W.K. Expression of P53 Oncoprotein in Non-Small-Cell Lung Cancer: A Favorable Prognostic Factor. J. Clin. Oncol. 1995, 13, 1893–1903. [Google Scholar] [CrossRef] [PubMed]
  114. Fan, Z.; Zhang, Q.; Feng, L.; Wang, L.; Zhou, X.; Han, J.; Li, D.; Liu, J.; Zhang, X.; Zuo, J.; et al. Genomic Landscape and Prognosis of Patients with TP53-Mutated Non-Small Cell Lung Cancer. Ann. Transl. Med. 2022, 10, 188. [Google Scholar] [CrossRef] [PubMed]
  115. Zhang, Y.; Williams-Villalobo, A.; Godavarthi, J.D.; Shakoor, F.; Xiong, S.; Liu, B. Integrative Bioinformatic Analysis of P53 and Pathway Alterations in Two Different Lung Cancer Subtypes. Biochem. Biophys. Rep. 2023, 33, 101404. [Google Scholar] [CrossRef] [PubMed]
  116. Gandara, D.R.; Hammerman, P.S.; Sos, M.L.; Lara, P.N.; Hirsch, F.R. Squamous Cell Lung Cancer: From Tumor Genomics to Cancer Therapeutics. Clin. Cancer Res. 2015, 21, 2236–2243. [Google Scholar] [CrossRef] [PubMed]
  117. Burns, D.M.; Anderson, C.M.; Gray, N. Do Changes in Cigarette Design Influence the Rise in Adenocarcinoma of the Lung? Cancer Causes Control 2011, 22, 13–22. [Google Scholar] [CrossRef] [PubMed]
  118. Khuder, S.A.; Mutgi, A.B. Effect of Smoking Cessation on Major Histologic Types of Lung Cancer. Chest 2001, 120, 1577–1583. [Google Scholar] [CrossRef]
  119. Dotto, G.P.; Rustgi, A.K. Squamous Cell Cancers: A Unified Perspective on Biology and Genetics. Cancer Cell 2016, 29, 622–637. [Google Scholar] [CrossRef] [PubMed]
  120. Hammerman, P.S.; Voet, D.; Lawrence, M.S.; Voet, D.; Jing, R.; Cibulskis, K.; Sivachenko, A.; Stojanov, P.; McKenna, A.; Lander, E.S.; et al. Comprehensive Genomic Characterization of Squamous Cell Lung Cancers. Nature 2012, 489, 519–525. [Google Scholar] [CrossRef]
  121. Kim, Y.; Hammerman, P.S.; Kim, J.; Yoon, J.A.; Lee, Y.; Sun, J.M.; Wilkerson, M.D.; Pedamallu, C.S.; Cibulskis, K.; Yoo, Y.K.; et al. Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients. J. Clin. Oncol. 2014, 32, 121–128. [Google Scholar] [CrossRef]
  122. Van Egeren, D.; Kohli, K.; Warner, J.L.; Bedard, P.L.; Riely, G.; Lepisto, E.; Schrag, D.; Lenoue-Newton, M.; Catalano, P.; Kehl, K.L.; et al. Genomic Analysis of Early-Stage Lung Cancer Reveals a Role for TP53 Mutations in Distant Metastasis. Sci. Rep. 2022, 12, 19055. [Google Scholar] [CrossRef] [PubMed]
  123. Robles, A.I.; Linke, S.P.; Harris, C.C. The P53 Network in Lung Carcinogenesis. Oncogene 2002, 21, 6898–6907. [Google Scholar] [CrossRef] [PubMed]
  124. Hainaut, P.; Pfeifer, G.P. Patterns of P53 G-->T Transversions in Lung Cancers Reflect the Primary Mutagenic Signature of DNA-Damage by Tobacco Smoke. Carcinogenesis 2001, 22, 367–374. [Google Scholar] [CrossRef] [PubMed]
  125. Denissenko, M.F.; Pao, A.; Tang, M.S.; Pfeifer, G.P. Preferential Formation of Benzo[a]Pyrene Adducts at Lung Cancer Mutational Hotspots in P53. Science 1996, 274, 430–432. [Google Scholar] [CrossRef] [PubMed]
  126. Smith, L.E.; Denissenko, M.F.; Bennett, W.P.; Li, H.; Amin, S.; Tang, M.S.; Pfeifer, G.P. Targeting of Lung Cancer Mutational Hotspots by Polycyclic Aromatic Hydrocarbons. J. Natl. Cancer Inst. 2000, 92, 803–811. [Google Scholar] [CrossRef] [PubMed]
  127. Heist, R.S.; Sequist, L.V.; Engelman, J.A. Genetic Changes in Squamous Cell Lung Cancer: A Review. J. Thorac. Oncol. 2012, 7, 924. [Google Scholar] [CrossRef] [PubMed]
  128. Cerami, E.; Gao, J.; Dogrusoz, U.; Gross, B.E.; Sumer, S.O.; Aksoy, A.; Jacobsen, A.; Byrne, C.J.; Heuer, M.L.; Larsson, E.; et al. The CBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discov. 2012, 2, 401–404. [Google Scholar] [CrossRef] [PubMed]
  129. de Bruijn, I.; Kundra, R.; Mastrogiacomo, B.; Tran, T.N.; Sikina, L.; Mazor, T.; Li, X.; Ochoa, A.; Zhao, G.; Lai, B.; et al. Analysis and Visualization of Longitudinal Genomic and Clinical Data from the AACR Project GENIE Biopharma Collaborative in CBioPortal. Cancer Res. 2023, 83, 3861–3867. [Google Scholar] [CrossRef] [PubMed]
  130. Gao, J.; Aksoy, B.A.; Dogrusoz, U.; Dresdner, G.; Gross, B.; Sumer, S.O.; Sun, Y.; Jacobsen, A.; Sinha, R.; Larsson, E.; et al. Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the CBioPortal. Sci. Signal 2013, 6, pl1. [Google Scholar] [CrossRef] [PubMed]
  131. Zhang, S.; Carlsen, L.; Hernandez Borrero, L.; Seyhan, A.A.; Tian, X.; El-Deiry, W.S. Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant P53 in Cancer. Biomolecules 2022, 12, 548. [Google Scholar] [CrossRef]
  132. Kamath, D.; Iwakuma, T.; Bossmann, S.H. Therapeutic Potential of Combating Cancer by Restoring Wild-Type P53 through MRNA Nanodelivery. Nanomedicine 2024, 56, 102732. [Google Scholar] [CrossRef] [PubMed]
  133. Wang, Z.; Burigotto, M.; Ghetti, S.; Vaillant, F.; Tan, T.; Capaldo, B.D.; Palmieri, M.; Hirokawa, Y.; Tai, L.; Simpson, D.S.; et al. Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival and Metastasis of a Broad Range of Cancer Cells. Cancer Discov. 2023, 14, 362–379. [Google Scholar] [CrossRef]
  134. Zhao, M.; Wang, T.; Gleber-Netto, F.O.; Chen, Z.; Mcgrail, D.J.; Gomez, J.A.; Ju, W.; Gadhikar, M.A.; Ma, W.; Shen, L.; et al. Mutant P53 Gains Oncogenic Functions through a Chromosomal Instability-Induced Cytosolic DNA Response. Nat. Commun. 2024, 15, 180. [Google Scholar] [CrossRef]
  135. Oren, M.; Rotter, V. Mutant P53 Gain-of-Function in Cancer. Cold Spring Harb. Perspect. Biol. 2010, 2, a001107. [Google Scholar] [CrossRef] [PubMed]
  136. Olive, K.P.; Tuveson, D.A.; Ruhe, Z.C.; Yin, B.; Willis, N.A.; Bronson, R.T.; Crowley, D.; Jacks, T. Mutant P53 Gain of Function in Two Mouse Models of Li-Fraumeni Syndrome. Cell 2004, 119, 847–860. [Google Scholar] [CrossRef]
  137. Alvarado-Ortiz, E.; de la Cruz-López, K.G.; Becerril-Rico, J.; Sarabia-Sánchez, M.A.; Ortiz-Sánchez, E.; García-Carrancá, A. Mutant P53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches. Front. Cell Dev. Biol. 2021, 8, 607670. [Google Scholar] [CrossRef]
  138. Huang, Y.; Jiao, Z.; Fu, Y.; Hou, Y.; Sun, J.; Hu, F.; Yu, S.; Gong, K.; Liu, Y.; Zhao, G. An Overview of the Functions of P53 and Drugs Acting Either on Wild- or Mutant-Type P53. Eur. J. Med. Chem. 2024, 265, 116121. [Google Scholar] [CrossRef]
  139. Yue, X.; Zhao, Y.; Xu, Y.; Zheng, M.; Feng, Z.; Hu, W. Mutant P53 in Cancer: Accumulation, Gain-of-Function, and Therapy. J. Mol. Biol. 2017, 429, 1595–1606. [Google Scholar] [CrossRef] [PubMed]
  140. Saini, H.; Choudhary, M.; Sharma, H.; Chowdhury, S.; Mukherjee, S.; Chowdhury, R. Chloroquine Induces Transitory Attenuation of Proliferation of Human Lung Cancer Cells through Regulation of Mutant P53 and YAP. Mol. Biol. Rep. 2023, 50, 1045–1058. [Google Scholar] [CrossRef]
  141. Mandinova, A.; Lee, S.W. The P53 Pathway as a Target in Cancer Therapeutics: Obstacles and Promise. Sci. Transl. Med. 2011, 3, 64rv1. [Google Scholar] [CrossRef]
  142. Barta, J.A.; Pauley, K.; Kossenkov, A.V.; McMahon, S.B. The Lung-Enriched P53 Mutants V157F and R158L/P Regulate a Gain of Function Transcriptome in Lung Cancer. Carcinogenesis 2020, 41, 67–77. [Google Scholar] [CrossRef] [PubMed]
  143. Cheng, Y.W.; Wu, M.F.; Wang, J.; Yeh, K.T.; Goan, Y.G.; Chiou, H.L.; Chen, C.Y.; Lee, H. Human Papillomavirus 16/18 E6 Oncoprotein Is Expressed in Lung Cancer and Related with P53 Inactivation. Cancer Res. 2007, 67, 10686–10693. [Google Scholar] [CrossRef] [PubMed]
  144. Kong, L.R.; Ong, R.W.; Tan, T.Z.; Mohamed Salleh, N.A.B.; Thangavelu, M.; Chan, J.V.; Koh, L.Y.J.; Periyasamy, G.; Lau, J.A.; Le, T.B.U.; et al. Targeting Codon 158 P53-Mutant Cancers via the Induction of P53 Acetylation. Nat. Commun. 2020, 11, 2086. [Google Scholar] [CrossRef] [PubMed]
  145. Wu, D.W.; Liu, W.S.; Wang, J.; Chen, C.Y.; Cheng, Y.W.; Lee, H. Reduced P21(WAF1/CIP1) via Alteration of P53-DDX3 Pathway Is Associated with Poor Relapse-Free Survival in Early-Stage Human Papillomavirus-Associated Lung Cancer. Clin. Cancer Res. 2011, 17, 1895–1905. [Google Scholar] [CrossRef] [PubMed]
  146. Feldser, D.M.; Kostova, K.K.; Winslow, M.M.; Taylor, S.E.; Cashman, C.; Whittaker, C.A.; Sanchez-Rivera, F.J.; Resnick, R.; Bronson, R.; Hemann, M.T.; et al. Stage-Specific Sensitivity to P53 Restoration during Lung Cancer Progression. Nature 2010, 468, 572–575. [Google Scholar] [CrossRef] [PubMed]
  147. Hu, X.; Estecio, M.R.; Chen, R.; Reuben, A.; Wang, L.; Fujimoto, J.; Carrot-Zhang, J.; McGranahan, N.; Ying, L.; Fukuoka, J.; et al. Evolution of DNA Methylome from Precancerous Lesions to Invasive Lung Adenocarcinomas. Nat. Commun. 2021, 12, 687. [Google Scholar] [CrossRef] [PubMed]
  148. Teixeira, V.H.; Pipinikas, C.P.; Pennycuick, A.; Lee-Six, H.; Chandrasekharan, D.; Beane, J.; Morris, T.J.; Karpathakis, A.; Feber, A.; Breeze, C.E.; et al. Deciphering the Genomic, Epigenomic, and Transcriptomic Landscapes of Pre-Invasive Lung Cancer Lesions. Nat. Med. 2019, 25, 517–525. [Google Scholar] [CrossRef]
  149. Wang, W.; El-Deiry, W.S. Restoration of P53 to Limit Tumor Growth. Curr. Opin. Oncol. 2008, 20, 90–96. [Google Scholar] [CrossRef] [PubMed]
  150. Andreeff, M.; Kelly, K.R.; Yee, K.; Assouline, S.; Strair, R.; Popplewell, L.; Bowen, D.; Martinelli, G.; Drummond, M.W.; Vyas, P.; et al. Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia. Clin. Cancer Res. 2016, 22, 868–876. [Google Scholar] [CrossRef]
  151. Fang, D.D.; Tang, Q.; Kong, Y.; Rong, T.; Wang, Q.; Li, N.; Fang, X.; Gu, J.; Xiong, D.; Yin, Y.; et al. MDM2 Inhibitor APG-115 Exerts Potent Antitumor Activity and Synergizes with Standard-of-Care Agents in Preclinical Acute Myeloid Leukemia Models. Cell Death Discov. 2021, 7, 90. [Google Scholar] [CrossRef]
  152. Wang, S.; Chen, F.E. Small-Molecule MDM2 Inhibitors in Clinical Trials for Cancer Therapy. Eur. J. Med. Chem. 2022, 236, 114334. [Google Scholar] [CrossRef] [PubMed]
  153. Kumar, A.; Hiran, T.; Holden, S.A.; Chafai-Fadela, K.; Rogers, S.; Ram, S.; Menon, K. Abstract 4470: KevetrinTM, a Novel Small Molecule, Activates P53, Enhances Expression of P21, Induces Cell Cycle Arrest and Apoptosis in a Human Cancer Cell Line. Cancer Res. 2011, 71, 4470. [Google Scholar] [CrossRef]
  154. Kumar, A.; Brennan, D.P.; Chafai-Fadela, K.; Holden, S.A.; Ram, S.; Shapiro, G.I.; Menon, K. Abstract 3221: Kevetrin Induces P53-Dependent and Independent Cell Cycle Arrest and Apoptosis in Ovarian Cancer Cell Lines Representing Heterogeneous Histologies. Cancer Res. 2017, 77, 3221. [Google Scholar] [CrossRef]
  155. Kumar, A.; Holden, S.A.; Chafai-Fadela, K.; Ram, S.; Menon, K. KevetrinTM Targets Both MDM2 P53 and Rb E2F Pathways in Tumor Suppression KevetrinTM Targets Both MDM2-P53 and Rb-E2F Pathways in Tumor Suppression. Cancer Res. 2012, 72, 2874. [Google Scholar] [CrossRef]
  156. Rangatia, J.; Vangala, R.K.; Singh, S.M.; Peer Zada, A.A.; Elsässer, A.; Kohlmann, A.; Haferlach, T.; Tenen, D.G.; Hiddemann, W.; Behre, G. Elevated C-Jun Expression in Acute Myeloid Leukemias Inhibits C/EBPalpha DNA Binding via Leucine Zipper Domain Interaction. Oncogene 2003, 22, 4760–4764. [Google Scholar] [CrossRef] [PubMed]
  157. Zhang, G.; An, Y.; Lu, X.; Zhong, H.; Zhu, Y.; Wu, Y.; Ma, F.; Yang, J.; Liu, Y.; Zhou, Z.; et al. A Novel Naphthalimide Compound Restores P53 Function in Non-Small Cell Lung Cancer by Reorganizing the Bak·Bcl-Xl Complex and Triggering Transcriptional Regulation. J. Biol. Chem. 2016, 291, 4211–4225. [Google Scholar] [CrossRef] [PubMed]
  158. Li, L.; Du, W.; Wang, H.; Zhao, Y.; Huang, Z.; Peng, Y.; Zeng, S.; Zhang, G. Small-Molecule MX-C2/3 Suppresses Non-Small Cell Lung Cancer Progression via P53 Activation. Chem. Biol. Interact. 2022, 366, 110142. [Google Scholar] [CrossRef] [PubMed]
  159. Chen, Z.; Fillmore, C.M.; Hammerman, P.S.; Kim, C.F.; Wong, K.K. Non-Small-Cell Lung Cancers: A Heterogeneous Set of Diseases. Nat. Rev. Cancer 2014, 14, 535–546. [Google Scholar] [CrossRef]
  160. Yuan, M.; Huang, L.L.; Chen, J.H.; Wu, J.; Xu, Q. The Emerging Treatment Landscape of Targeted Therapy in Non-Small-Cell Lung Cancer. Signal Transduct. Target. Ther. 2019, 4, 61. [Google Scholar] [CrossRef]
  161. Herbst, R.S.; Morgensztern, D.; Boshoff, C. The Biology and Management of Non-Small Cell Lung Cancer. Nature 2018, 553, 446–454. [Google Scholar] [CrossRef]
  162. Lau, S.C.M.; Pan, Y.; Velcheti, V.; Wong, K.K. Squamous Cell Lung Cancer: Current Landscape and Future Therapeutic Options. Cancer Cell 2022, 40, 1279–1293. [Google Scholar] [CrossRef] [PubMed]
  163. Yang, C.Y.; Yang, J.C.H.; Yang, P.C. Precision Management of Advanced Non-Small Cell Lung Cancer. Annu. Rev. Med. 2020, 71, 117–136. [Google Scholar] [CrossRef] [PubMed]
  164. Paik, P.K.; Pillai, R.N.; Lathan, C.S.; Velasco, S.A.; Papadimitrakopoulou, V. New Treatment Options in Advanced Squamous Cell Lung Cancer. Am. Soc. Clin. Oncol. Educ. Book 2019, 39, e198–e206. [Google Scholar] [CrossRef] [PubMed]
  165. Socinski, M.A.; Obasaju, C.; Gandara, D.; Hirsch, F.R.; Bonomi, P.; Bunn, P.A.; Kim, E.S.; Langer, C.J.; Natale, R.B.; Novello, S.; et al. Current and Emergent Therapy Options for Advanced Squamous Cell Lung Cancer. J. Thorac. Oncol. 2018, 13, 165–183. [Google Scholar] [CrossRef] [PubMed]
  166. Cumplido-Laso, G.; Benitez, D.A.; Mulero-Navarro, S.; Carvajal-Gonzalez, J.M. Transcriptional Regulation of Airway Epithelial Cell Differentiation: Insights into the Notch Pathway and Beyond. Int. J. Mol. Sci. 2023, 24, 14789. [Google Scholar] [CrossRef] [PubMed]
  167. Niu, Z.; Jin, R.; Zhang, Y.; Li, H. Signaling Pathways and Targeted Therapies in Lung Squamous Cell Carcinoma: Mechanisms and Clinical Trials. Signal Transduct. Target. Ther. 2022, 7, 1. [Google Scholar] [CrossRef]
  168. Kelland, L. The Resurgence of Platinum-Based Cancer Chemotherapy. Nat. Rev. Cancer 2007, 7, 573–584. [Google Scholar] [CrossRef] [PubMed]
  169. Rottenberg, S.; Disler, C.; Perego, P. The Rediscovery of Platinum-Based Cancer Therapy. Nat. Rev. Cancer 2021, 21, 37–50. [Google Scholar] [CrossRef] [PubMed]
  170. Brower, V. Predicting Response to Cisplatin in NSCLC. Lancet Oncol. 2007, 8, 674. [Google Scholar] [CrossRef]
  171. Arbour, K.C.; Riely, G.J. Systemic Therapy for Locally Advanced and Metastatic Non-Small Cell Lung Cancer: A Review. JAMA 2019, 322, 764–774. [Google Scholar] [CrossRef]
  172. Zhu, G.; Pan, C.; Bei, J.X.; Li, B.; Liang, C.; Xu, Y.; Fu, X. Mutant P53 in Cancer Progression and Targeted Therapies. Front. Oncol. 2020, 10, 595187. [Google Scholar] [CrossRef] [PubMed]
  173. Xu, F.; Lin, H.; He, P.; He, L.; Chen, J.; Lin, L.; Chen, Y. A TP53-Associated Gene Signature for Prediction of Prognosis and Therapeutic Responses in Lung Squamous Cell Carcinoma. Oncoimmunology 2020, 9, 1731943. [Google Scholar] [CrossRef]
  174. Huang, J. Current Developments of Targeting the P53 Signaling Pathway for Cancer Treatment. Pharmacol. Ther. 2021, 220, 107720. [Google Scholar] [CrossRef] [PubMed]
  175. Reck, M.; Schenker, M.; Lee, K.H.; Provencio, M.; Nishio, M.; Lesniewski-Kmak, K.; Sangha, R.; Ahmed, S.; Raimbourg, J.; Feeney, K.; et al. Nivolumab plus Ipilimumab versus Chemotherapy as First-Line Treatment in Advanced Non-Small-Cell Lung Cancer with High Tumour Mutational Burden: Patient-Reported Outcomes Results from the Randomised, Open-Label, Phase III CheckMate 227 Trial. Eur. J. Cancer 2019, 116, 137–147. [Google Scholar] [CrossRef]
  176. Wang, Y.; Goh, K.Y.; Chen, Z.; Lee, W.X.; Choy, S.M.; Fong, J.X.; Wong, Y.K.; Li, D.; Hu, F.; Tang, H.W. A Novel TP53 Gene Mutation Sustains Non-Small Cell Lung Cancer through Mitophagy. Cells 2022, 11, 3587. [Google Scholar] [CrossRef] [PubMed]
  177. Craig, D.J.; Crawford, E.L.; Chen, H.; Grogan, E.L.; Deppen, S.A.; Morrison, T.; Antic, S.L.; Massion, P.P.; Willey, J.C. TP53 Mutation Prevalence in Normal Airway Epithelium as a Biomarker for Lung Cancer Risk. BMC Cancer 2023, 23, 783. [Google Scholar] [CrossRef] [PubMed]
  178. Budczies, J.; Romanovsky, E.; Kirchner, M.; Neumann, O.; Blasi, M.; Schnorbach, J.; Shah, R.; Bozorgmehr, F.; Savai, R.; Stiewe, T.; et al. Abstract 2487: KRAS and TP53 Co-Mutation Predicts Benefit of Immune Checkpoint Blockade in Lung Adenocarcinoma. Cancer Res. 2024, 84, 2487. [Google Scholar] [CrossRef]
  179. Zhang, T.; Xu, Z.; Liu, G.; Jiang, B.; de Bock, G.H.; Groen, H.J.M.; Vliegenthart, R.; Xie, X. Simultaneous Identification of Egfr, Kras, Erbb2, and Tp53 Mutations in Patients with Non-Small Cell Lung Cancer by Machine Learning-Derived Three-Dimensional Radiomics. Cancers 2021, 13, 1814. [Google Scholar] [CrossRef]
  180. Qiao, H.; Ding, Z.; Zhu, Y.; Wei, Y.; Xiao, B.; Zhao, Y.; Feng, Q. Quantitative Analysis of TP53-Related Lung Cancer Based on Radiomics. Int. J. Gen. Med. 2022, 15, 8481. [Google Scholar] [CrossRef]
  181. Canale, M.; Andrikou, K.; Priano, I.; Cravero, P.; Pasini, L.; Urbini, M.; Delmonte, A.; Crinò, L.; Bronte, G.; Ulivi, P. The Role of TP53 Mutations in EGFR-Mutated Non-Small-Cell Lung Cancer: Clinical Significance and Implications for Therapy. Cancers 2022, 14, 1143. [Google Scholar] [CrossRef]
  182. Wang, S.; Jiang, M.; Yang, Z.; Huang, X.; Li, N. The Role of Distinct Co-Mutation Patterns with TP53 Mutation in Immunotherapy for NSCLC. Genes Dis. 2022, 9, 245–251. [Google Scholar] [CrossRef] [PubMed]
  183. Wang, X.; Ricciuti, B.; Nguyen, T.; Li, X.; Rabin, M.S.; Awad, M.M.; Lin, X.; Johnson, B.E.; Christiani, D.C. Association between Smoking History and Tumor Mutation Burden in Advanced Non⇓small Cell Lung Cancer. Cancer Res. 2021, 81, 2566–2573. [Google Scholar] [CrossRef]
  184. Lim, T.K.H.; Skoulidis, F.; Kerr, K.M.; Ahn, M.J.; Kapp, J.R.; Soares, F.A.; Yatabe, Y. KRAS G12C in Advanced NSCLC: Prevalence, Co-Mutations, and Testing. Lung Cancer 2023, 184, 107293. [Google Scholar] [CrossRef] [PubMed]
  185. Caron, E. Cellular Functions of the Rap1 GTP-Binding Protein: A Pattern Emerges. J. Cell Sci. 2003, 116, 435–440. [Google Scholar] [CrossRef]
  186. Jaffe, A.B.; Hall, A. Rho GTPases: Biochemistry and Biology. Annu. Rev. Cell Dev. Biol. 2005, 21, 247–269. [Google Scholar] [CrossRef] [PubMed]
  187. Khanna, A.; Lotfi, P.; Chavan, A.J.; Montaño, N.M.; Bolourani, P.; Weeks, G.; Shen, Z.; Briggs, S.P.; Pots, H.; Van Haastert, P.J.M.; et al. The Small GTPases Ras and Rap1 Bind to and Control TORC2 Activity. Sci. Rep. 2016, 6, 25823. [Google Scholar] [CrossRef] [PubMed]
  188. Croft, D.R.; Crighton, D.; Samuel, M.S.; Lourenco, F.C.; Munro, J.; Wood, J.; Bensaad, K.; Vousden, K.H.; Sansom, O.J.; Ryan, K.M.; et al. P53-Mediated Transcriptional Regulation and Activation of the Actin Cytoskeleton Regulatory RhoC to LIMK2 Signaling Pathway Promotes Cell Survival. Cell Res. 2011, 21, 666–682. [Google Scholar] [CrossRef]
  189. Tuncbag, N.; Kar, G.; Gursoy, A.; Keskin, O.; Nussinov, R. Towards Inferring Time Dimensionality in Protein-Protein Interaction Networks by Integrating Structures: The P53 Example. Mol. Biosyst. 2009, 5, 1770–1778. [Google Scholar] [CrossRef]
  190. George, J.; Lim, J.S.; Jang, S.J.; Cun, Y.; Ozretia, L.; Kong, G.; Leenders, F.; Lu, X.; Fernández-Cuesta, L.; Bosco, G.; et al. Comprehensive Genomic Profiles of Small Cell Lung Cancer. Nature 2015, 524, 47–53. [Google Scholar] [CrossRef]
  191. Knight, S.B.; Crosbie, P.A.; Balata, H.; Chudziak, J.; Hussell, T.; Dive, C. Progress and Prospects of Early Detection in Lung Cancer. Open Biol. 2017, 7, 170070. [Google Scholar] [CrossRef]
  192. Jiang, W.; Cheng, H.; Yu, L.; Zhang, J.; Wang, Y.; Liang, Y.; Lou, F.; Wang, H.; Cao, S. Mutation Patterns and Evolutionary Action Score of TP53 Enable Identification of a Patient Population with Poor Prognosis in Advanced Non-Small Cell Lung Cancer. Cancer Med. 2023, 12, 6649–6658. [Google Scholar] [CrossRef] [PubMed]
  193. Yu, L.; Liang, X.; Wang, J.; Ding, G.; Tang, J.; Xue, J.; He, X.; Ge, J.; Jin, X.; Yang, Z.; et al. Identification of Key Biomarkers and Candidate Molecules in Non-Small-Cell Lung Cancer by Integrated Bioinformatics Analysis. Genet. Res. 2023, 2023, e29. [Google Scholar] [CrossRef] [PubMed]
  194. Hainaut, P.; Pfeifer, G.P. Somatic TP53 Mutations in the Era of Genome Sequencing. Cold Spring Harb. Perspect. Med. 2016, 6, a026179. [Google Scholar] [CrossRef] [PubMed]
  195. Choi, Y.J.; Lee, K.; Lee, S.Y.; Kwon, Y.; Woo, J.; Jeon, C.Y.; Ko, S.G. P53 Activation Enhances the Sensitivity of Non-Small Cell Lung Cancer to the Combination of SH003 and Docetaxel by Inhibiting de Novo Pyrimidine Synthesis. Cancer Cell Int. 2024, 24, 156. [Google Scholar] [CrossRef] [PubMed]
  196. Wang, L.; Wu, P.; Shen, Z.; Yu, Q.; Zhang, Y.; Ye, F.; Chen, K.; Zhao, J. An Immune Checkpoint-Based Signature Predicts Prognosis and Chemotherapy Response for Patients with Small Cell Lung Cancer. Int. Immunopharmacol. 2023, 117, 109827. [Google Scholar] [CrossRef] [PubMed]
  197. Mendoza, R.P.; Chen-Yost, H.I.H.; Wanjari, P.; Wang, P.; Symes, E.; Johnson, D.N.; Reeves, W.; Mueller, J.; Antic, T.; Biernacka, A. Lung Adenocarcinomas with Isolated TP53 Mutation: A Comprehensive Clinical, Cytopathologic and Molecular Characterization. Cancer Med. 2024, 13, e6873. [Google Scholar] [CrossRef] [PubMed]
  198. Alam, M.; Hasan, G.M.; Eldin, S.M.; Adnan, M.; Riyaz, M.B.; Islam, A.; Khan, I.; Hassan, M.I. Investigating Regulated Signaling Pathways in Therapeutic Targeting of Non-Small Cell Lung Carcinoma. Biomed. Pharmacother. 2023, 161, 114452. [Google Scholar] [CrossRef] [PubMed]
  199. Basse, C.; Trabelsi-Grati, O.; Masliah, J.; Callens, C.; Kamal, M.; Freneaux, P.; Klijanienko, J.; Bieche, I.; Girard, N. Gain of Aggressive Histological and Molecular Patterns after Acquired Resistance to Novel Anti-EGFR Therapies in Non-Small Cell Lung Cancer. Int. J. Mol. Sci. 2023, 24, 3802. [Google Scholar] [CrossRef]
  200. Zeng, J.; Ding, X.; Ding, J.; Wang, X. Histological Transformation into SCLC: An Important Resistance Mechanism of NSCLC upon Immunotherapy. Front. Immunol. 2023, 14, 1275957. [Google Scholar] [CrossRef]
  201. Niu, X.; Martinez, L. Harnessing P53 to Improve Immunotherapy for Lung Cancer Treatment. Cancer Res. 2023, 84, OF1–OF2. [Google Scholar] [CrossRef]
  202. Zhu, M.; Kim, J.; Deng, Q.; Ricciuti, B.; Alessi, J.V.; Eglenen-Polat, B.; Bender, M.E.; Huang, H.C.; Kowash, R.R.; Cuevas, I.; et al. Loss of P53 and Mutational Heterogeneity Drives Immune Resistance in an Autochthonous Mouse Lung Cancer Model with High Tumor Mutational Burden. Cancer Cell 2023, 41, 1731–1748.e8. [Google Scholar] [CrossRef] [PubMed]
  203. Goto, T.; Kunimasa, K.; Hirotsu, Y.; Nakagomi, T.; Yokoyama, Y.; Higuchi, R.; Otake, S.; Oyama, T.; Amemiya, K.; Mochizuki, H.; et al. Association of Mutation Profiles with Postoperative Survival in Patients with Non-Small Cell Lung Cancer. Cancers 2020, 12, 3472. [Google Scholar] [CrossRef] [PubMed]
  204. de Jager, V.D.; Timens, W.; Bayle, A.; Botling, J.; Brcic, L.; Büttner, R.; Fernandes, M.G.O.; Havel, L.; Hochmair, M.; Hofman, P.; et al. Future Perspective for the Application of Predictive Biomarker Testing in Advanced Stage Non-Small Cell Lung Cancer. Lancet Reg. Health Eur. 2024, 38, 100839. [Google Scholar] [CrossRef] [PubMed]
  205. Shahid, A.; Chen, M.; Yeung, S.; Parsa, C.; Orlando, R.; Huang, Y. The Medicinal Mushroom Ganoderma Lucidum Prevents Lung Tumorigenesis Induced by Tobacco Smoke Carcinogens. Front. Pharmacol. 2023, 14, 1244150. [Google Scholar] [CrossRef] [PubMed]
  206. Rudrapal, M.; Maji, S.; Prajapati, S.K.; Kesharwani, P.; Deb, P.K.; Khan, J.; Ismail, R.M.; Kankate, R.S.; Sahoo, R.K.; Khairnar, S.J.; et al. Protective Effects of Diets Rich in Polyphenols in Cigarette Smoke (CS)-Induced Oxidative Damages and Associated Health Implications. Antioxidants 2022, 11, 1217. [Google Scholar] [CrossRef] [PubMed]
  207. Boța, M.; Vlaia, L.; Jîjie, A.-R.; Marcovici, I.; Crişan, F.; Oancea, C.; Dehelean, C.A.; Mateescu, T.; Moacă, E.-A. Exploring Synergistic Interactions between Natural Compounds and Conventional Chemotherapeutic Drugs in Preclinical Models of Lung Cancer. Pharmaceuticals 2024, 17, 598. [Google Scholar] [CrossRef] [PubMed]
  208. Ding, Y.; Hou, R.; Yu, J.; Xing, C.; Zhuang, C.; Qu, Z. Dietary Phytochemicals as Potential Chemopreventive Agents against Tobacco-Induced Lung Carcinogenesis. Nutrients 2023, 15, 491. [Google Scholar] [CrossRef] [PubMed]
  209. Sompel, K.; Smith, A.J.; Hauer, C.; Elango, A.P.; Clamby, E.T.; Keith, R.L.; Tennis, M.A. Precision Cut Lung Slices as a Preclinical Model for Non-Small Cell Lung Cancer Chemoprevention. Cancer Prev. Res. 2023, 16, 247–258. [Google Scholar] [CrossRef]
  210. Kordiak, J.; Bielec, F.; Jabłoński, S.; Pastuszak-Lewandoska, D. Role of Beta-Carotene in Lung Cancer Primary Chemoprevention: A Systematic Review with Meta-Analysis and Meta-Regression. Nutrients 2022, 14, 1361. [Google Scholar] [CrossRef]
  211. Benusiglio, P.R.; Fallet, V.; Sanchis-Borja, M.; Coulet, F.; Cadranel, J. Lung Cancer Is Also a Hereditary Disease. Eur. Respir. Rev. 2021, 30, 210045. [Google Scholar] [CrossRef]
  212. Mezquita, L.; Jové, M.; Nadal, E.; Kfoury, M.; Morán, T.; Ricordel, C.; Dhooge, M.; Tlemsani, C.; Léna, H.; Teulé, A.; et al. High Prevalence of Somatic Oncogenic Driver Alterations in Patients with NSCLC and Li-Fraumeni Syndrome. J. Thorac. Oncol. 2020, 15, 1232–1239. [Google Scholar] [CrossRef]
  213. Butt, H.; Munchel, A.; York, T.; Macatangay, R. Multi-Generational Review of Oncologic Tumors in a Family with TP53 Mutation Presenting with a Pediatric Patient with Osteosarcoma and Lung Acinar Adenocarcinoma. Cureus 2021, 13, e17271. [Google Scholar] [CrossRef]
  214. Nierengarten, M.B. Updated American Cancer Society Lung Cancer Screening Guidelines: The New Guidelines Offer Expanded Criteria Recommended for Lung Cancer Screening Based on Age, Smoking Status, and Smoking History. Cancer 2024, 130, 656–657. [Google Scholar] [CrossRef] [PubMed]
  215. Kim, Y.; Lee, J.; Lee, E.; Lim, J.; Kim, Y.; Lee, C.T.; Jang, S.H.; Paek, Y.J.; Lee, W.C.; Lee, C.W.; et al. Strategies to Improve Smoking Cessation for Participants in Lung Cancer Screening Program: Analysis of Factors Associated with Smoking Cessation in Korean Lung Cancer Screening Project (K-LUCAS). Cancer Res. Treat. 2024, 56, 92–103. [Google Scholar] [CrossRef]
  216. Bandi, P.; Star, J.; Ashad-Bishop, K.; Kratzer, T.; Smith, R.; Jemal, A. Lung Cancer Screening in the US, 2022. JAMA Intern. Med. 2024. [Google Scholar] [CrossRef] [PubMed]
  217. Smith, P.; Murray, R.L.; Crosbie, P.A. Integrated Stop Smoking Interventions Are Essential to Maximise the Health Benefits from Lung Cancer Screening. Thorax 2024, 79, 198–199. [Google Scholar] [CrossRef] [PubMed]
  218. Pillay, J.; Rahman, S.; Klarenbach, S.; Reynolds, D.L.; Tessier, L.A.; Thériault, G.; Persaud, N.; Finley, C.; Leighl, N.; McInnes, M.D.F.; et al. Screening for Lung Cancer with Computed Tomography: Protocol for Systematic Reviews for the Canadian Task Force on Preventive Health Care. Syst. Rev. 2024, 13, 88. [Google Scholar] [CrossRef]
  219. Toumazis, I.; Cao, P.; de Nijs, K.; Bastani, M.; Munshi, V.; Hemmati, M.; ten Haaf, K.; Jeon, J.; Tammemägi, M.; Gazelle, G.S.; et al. Risk Model-Based Lung Cancer Screening: A Cost-Effectiveness Analysis. Ann. Intern. Med. 2023, 176, 320–332. [Google Scholar] [CrossRef]
  220. Mukhopadhyay, S.; Huang, H.Y.; Lin, Z.; Ranieri, M.; Li, S.; Sahu, S.; Liu, Y.; Ban, Y.; Guidry, K.; Hu, H.; et al. Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy. Cancer Res. 2023, 83, 4095–4111. [Google Scholar] [CrossRef]
  221. Liu, F.; Xin, M.; Feng, H.; Zhang, W.; Liao, Z.; Sheng, T.; Wen, P.; Wu, Q.; Liang, T.; Shi, J.; et al. Cryo-Shocked Tumor Cells Deliver CRISPR-Cas9 for Lung Cancer Regression by Synthetic Lethality. Sci. Adv. 2024, 10, eadk8264. [Google Scholar] [CrossRef]
  222. Yang, Z.; Liang, S.Q.; Zhao, L.; Yang, H.; Marti, T.M.; Hegedüs, B.; Gao, Y.; Zheng, B.; Chen, C.; Wang, W.; et al. Metabolic Synthetic Lethality by Targeting NOP56 and MTOR in KRAS-Mutant Lung Cancer. J. Exp. Clin. Cancer Res. 2022, 41, 88. [Google Scholar] [CrossRef] [PubMed]
  223. Long, L.L.; Ma, S.C.; Guo, Z.Q.; Zhang, Y.P.; Fan, Z.; Liu, L.J.; Liu, L.; Han, D.D.; Leng, M.X.; Wang, J.; et al. PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer. Cancer Res. 2023, 83, 568–581. [Google Scholar] [CrossRef] [PubMed]
  224. Zhang, S.S.; Nagasaka, M. Spotlight on Sotorasib (AMG 510) for KRAS G12C Positive Non-Small Cell Lung Cancer. Lung Cancer 2021, 12, 115–122. [Google Scholar] [CrossRef] [PubMed]
  225. Riganti, C.; Giampietro, R.; Kopecka, J.; Costamagna, C.; Abatematteo, F.S.; Contino, M.; Abate, C. MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor. Int. J. Mol. Sci. 2020, 21, 3333. [Google Scholar] [CrossRef] [PubMed]
  226. Chandarana, C.; Tiwari, A. A Review of Clinical Trials of Cancer and Its Treatment as a Vaccine. Rev. Recent Clin. Trials 2024, 19, 7–33. [Google Scholar] [CrossRef] [PubMed]
  227. Ji, D.; Zhang, Y.; Sun, J.; Zhang, B.; Ma, W.; Cheng, B.; Wang, X.; Li, Y.; Mu, Y.; Xu, H.; et al. An Engineered Influenza Virus to Deliver Antigens for Lung Cancer Vaccination. Nat. Biotechnol. 2024, 42, 518–528. [Google Scholar] [CrossRef]
  228. Sathish, G.; Monavarshini, L.K.; Sundaram, K.; Subramanian, S.; Kannayiram, G. Immunotherapy for Lung Cancer. Pathol. Res. Pract. 2024, 254, 155104. [Google Scholar] [CrossRef] [PubMed]
  229. Kumar, S.; Malviya, R.; Uniyal, P. Vaccine for Targeted Therapy of Lung Cancer: Advances and Developments. Curr. Drug Targets 2024, 25, 1–4. [Google Scholar] [CrossRef] [PubMed]
  230. Li, W.; Huang, J.; Shen, C.; Jiang, W.; Yang, X.; Huang, J.; Gu, Y.; Li, Z.; Ma, Y.; Bian, J. Tumor-Targeted Metabolic Inhibitor Prodrug Labelled with Cyanine Dyes Enhances Immunoprevention of Lung Cancer. Acta Pharm. Sin. B 2024, 14, 751–764. [Google Scholar] [CrossRef]
  231. Zeng, W.; Pan, J.; Fang, Z.; Jia, J.; Zhang, R.; He, M.; Zhong, H.; He, J.; Yang, X.; Shi, Y.; et al. A Novel PD-L1-Containing MSLN Targeting Vaccine for Lung Cancer Immunotherapy. Front. Immunol. 2022, 13, 925217. [Google Scholar] [CrossRef]
  232. Yuan, B.; Clowers, M.J.; Velasco, W.V.; Peng, S.; Peng, Q.; Shi, Y.; Ramos-Castaneda, M.; Zarghooni, M.; Yang, S.; Babcock, R.L.; et al. Targeting IL-1β as an Immunopreventive and Therapeutic Modality for K-Ras-Mutant Lung Cancer. JCI Insight 2022, 7, e157788. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Summary overview of the p53 pathway. In normal conditions (right panel), the p53 protein is strongly negatively regulated by MDM2/MDMX, an E3 ligase that ubiquitinates p53, leading to its degradation in the proteasome. Under stress conditions, generated by extracellular and intracellular stress (left panel), p53 levels increase, and through post-translational modifications (e.g., phosphorylation, acetylation, and methylation), p53 is activated and stabilized. In the cell nucleus, p53 tetramers bind to DNA through p53 response elements (p53REs), regulating the transcription of genes that control various biological processes.
Figure 1. Summary overview of the p53 pathway. In normal conditions (right panel), the p53 protein is strongly negatively regulated by MDM2/MDMX, an E3 ligase that ubiquitinates p53, leading to its degradation in the proteasome. Under stress conditions, generated by extracellular and intracellular stress (left panel), p53 levels increase, and through post-translational modifications (e.g., phosphorylation, acetylation, and methylation), p53 is activated and stabilized. In the cell nucleus, p53 tetramers bind to DNA through p53 response elements (p53REs), regulating the transcription of genes that control various biological processes.
Biomedicines 12 01453 g001
Figure 2. Genetic alterations of p53 in the different types of lung cancer from cBioPortal datasets. (a) Distribution of p53 mutation type in LUAD (N = 221), NSCLC (N = 240), SCLC (N = 110), and LUSC (N = 175). (b) Point mutations within the p53 gene in LUSC patients. Green, red, and violet boxes correspond to transactivation domain, DNA-binding domain, and oligomerization domain, respectively.
Figure 2. Genetic alterations of p53 in the different types of lung cancer from cBioPortal datasets. (a) Distribution of p53 mutation type in LUAD (N = 221), NSCLC (N = 240), SCLC (N = 110), and LUSC (N = 175). (b) Point mutations within the p53 gene in LUSC patients. Green, red, and violet boxes correspond to transactivation domain, DNA-binding domain, and oligomerization domain, respectively.
Biomedicines 12 01453 g002
Figure 3. Mutant p53 in cancer. Mutations of p53 can lead to various oncogenic effects, referred to as GOF, among which are metabolic adaptations, genomic instability, tumorigenesis, metastasis, and increased resistance to anticancer treatments. Negative dominant effects on the wild-type protein as well as LOF of the wild-type p53 protein include promoting proliferation, survival, and conferring metastatic potential to cells.
Figure 3. Mutant p53 in cancer. Mutations of p53 can lead to various oncogenic effects, referred to as GOF, among which are metabolic adaptations, genomic instability, tumorigenesis, metastasis, and increased resistance to anticancer treatments. Negative dominant effects on the wild-type protein as well as LOF of the wild-type p53 protein include promoting proliferation, survival, and conferring metastatic potential to cells.
Biomedicines 12 01453 g003
Figure 4. Relation of TP53 gene expression in LUSC patients from cBioPortal datasets with RAP1A gene expression (a) and RHOC gene expression (b).
Figure 4. Relation of TP53 gene expression in LUSC patients from cBioPortal datasets with RAP1A gene expression (a) and RHOC gene expression (b).
Biomedicines 12 01453 g004
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Benitez, D.A.; Cumplido-Laso, G.; Olivera-Gómez, M.; Del Valle-Del Pino, N.; Díaz-Pizarro, A.; Mulero-Navarro, S.; Román-García, A.; Carvajal-Gonzalez, J.M. p53 Genetics and Biology in Lung Carcinomas: Insights, Implications and Clinical Applications. Biomedicines 2024, 12, 1453. https://doi.org/10.3390/biomedicines12071453

AMA Style

Benitez DA, Cumplido-Laso G, Olivera-Gómez M, Del Valle-Del Pino N, Díaz-Pizarro A, Mulero-Navarro S, Román-García A, Carvajal-Gonzalez JM. p53 Genetics and Biology in Lung Carcinomas: Insights, Implications and Clinical Applications. Biomedicines. 2024; 12(7):1453. https://doi.org/10.3390/biomedicines12071453

Chicago/Turabian Style

Benitez, Dixan A., Guadalupe Cumplido-Laso, Marcos Olivera-Gómez, Nuria Del Valle-Del Pino, Alba Díaz-Pizarro, Sonia Mulero-Navarro, Angel Román-García, and Jose Maria Carvajal-Gonzalez. 2024. "p53 Genetics and Biology in Lung Carcinomas: Insights, Implications and Clinical Applications" Biomedicines 12, no. 7: 1453. https://doi.org/10.3390/biomedicines12071453

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop