Search Results (191)

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article

Proto-oncogenes in the RAS superfamily play dual roles in maintaining cellular homeostasis, such as regulating growth signals and contributing to cancer development through proliferation and deregulation. Activating proto-oncogenes in vitro transforms cells, underscoring their centrality in gene regulation and cellular networks. Despite decades of research, poor outcomes in advanced cancers reveal gaps in understanding Ras-driven mechanisms or therapeutic strategies. This narrative review examines RAS genes and Ras proteins in both housekeeping functions, such as cell growth, apoptosis, and protein trafficking, as well as in tumorigenesis, integrating insights from human (HRAS, KRAS, NRAS), mouse (Hras, Kras, Nras), and Drosophila melanogaster (ras) models. While RAS mutations are tightly linked to human tumors, the interplay between their standard and oncogenic functions remains complex. Even within the same tissue, distinct cancer pathways—such as the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways—can drive varied disease courses, complicating treatment. Advanced-stage cancers add further challenges, including heterogeneity, protective microenvironments, drug resistance, and adaptive progression. This synthesis organizes current knowledge of RAS gene regulation and Ras protein function from genomic alterations and intracellular signaling to membrane dynamics and extracellular interactions, offering a layered perspective on the Ras pathway’s role in both housekeeping and tumorigenic contexts. Full article

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, comprises embryonal (ERMS) and alveolar (ARMS) subtypes with distinct histopathological features, clinical outcomes, and therapeutic responses. To better characterize their molecular distinctions, we performed untargeted plasma proteomics and metabolomics profiling in children with ERMS (n = 18), ARMS (n = 17), and matched healthy controls (n = 18). Differential expression, functional enrichment (GO, KEGG, RaMP-DB), co-expression network analysis (WGCNA/WMCNA), and multi-omics integration (DIABLO, MOFA) revealed distinct molecular signatures for each subtype. ARMS displayed elevated oncogenic and stemness-associated proteins (e.g., cyclin E1, FAP, myotrophin) and metabolites involved in lipid transport, fatty acid metabolism, and polyamine biosynthesis. In contrast, ERMS was enriched in immune-related and myogenic proteins (e.g., myosin-9, SAA2, S100A11) and metabolites linked to glutamate/glycine metabolism and redox homeostasis. Pathway analyses highlighted subtype-specific activation of PI3K-Akt and Hippo signaling in ARMS and immune and coagulation pathways in ERMS. Additionally, the proteomics and metabolomics datasets showed association with clinical parameters, including disease stage, lymph node involvement, and age, demonstrating clear molecular discrimination consistent with clinical observation. Co-expression networks and integrative analyses further reinforced these distinctions, uncovering coordinated protein–metabolite modules. Our findings reveal novel, subtype-specific molecular programs in RMS and propose candidate biomarkers and pathways that may guide precision diagnostics and therapeutic targeting in pediatric sarcomas. Full article

High-grade osteosarcoma (HGOS) is the most common primary malignant bone tumor in children and adolescents. Poor response to chemotherapy is linked to worse prognosis and increased risk of recurrence and metastasis. However, current assessment methods, such as tumor necrosis evaluation, are time-consuming and delay treatment decisions. Thus, identifying molecular pathways and predictive biomarkers is essential for guiding early therapeutic strategies. In this study, RNA-seq analysis of HGOS tissues revealed enrichment of cholesterol biosynthesis and mitotic pathways in poor responders. Additionally, high HMGCR expression, as analyzed from TCGA data, was associated with poor prognosis in sarcoma. Functional validation using SaOS-2 cells, which exhibited poor drug sensitivity and elevated HMGCR levels, demonstrated that simvastatin enhanced the efficacy of cisplatin and doxorubicin by inducing mitochondrial-mediated apoptosis and downregulating anti-apoptotic proteins. Simvastatin also reduced cell migration and invasion by suppressing epithelial–mesenchymal transition and extracellular matrix degradation. Mechanistically, simvastatin disrupted Ras prenylation and inhibited downstream oncogenic signaling pathways, including Akt/mTOR and Akt/GSK3, which regulate survival and metastasis-associated gene expression. These findings suggest that the cholesterol biosynthesis pathway particularly plays a critical role in chemoresistance and metastasis in HGOS and may serve as a promising predictive molecular target for guiding early therapeutic strategies. Full article

Ras signaling regulates many cellular processes in cancer development. While well-known Ras-related oncogenes, such as KRAS, have been extensively explored, the role of other Ras-related genes in cancer remains poorly studied. Dexamethasone-induced Ras-related protein 1 (RASD1), a member of the Ras superfamily, is widely expressed across various tissues and is involved in inhibiting cell growth and inducing apoptosis, suggesting a potential role as a tumor suppressor. Here, we investigated RASD1 expression across multiple tissues and cancers, utilizing data from The Cancer Genome Atlas (TCGA), Human Protein Atlas, and Genotype-Tissue Expression (GTEx) databases. Our analysis revealed a significant downregulation of RASD1 mRNA expression in several cancer types compared to normal tissues, correlating with low levels of promoter methylation. Interestingly, high RASD1 expression correlated with a favorable prognosis in multiple cancers. Immune cell infiltration analysis indicated that elevated RASD1 expression is associated with an increased infiltration of CD4⁺ T cells and myeloid-derived dendritic cells in cancer. Furthermore, the expression of genes exhibiting similar expression patterns as RASD1 suggest that RASD1 may play a role in interleukin-4-mediated apoptosis and could regulate the transcription of the phosphatase and tensin homolog (PTEN) gene. Overall, these findings suggest that RASD1 may modulate immune signaling and tumor suppressive pathways. Full article

This review examines the prevalence, molecular mechanisms, and clinical implications of RAS mutations in Central Nervous System (CNS) tumors, with a particular focus on glioblastoma. We summarize the current understanding of RAS-driven oncogenic pathways, their contribution to tumor progression, and potential therapeutic strategies targeting RAS and its downstream effectors. Although direct RAS mutations are rare in primary CNS tumors, alterations in RAS signaling, such as NF-1 loss and aberrant receptor tyrosine kinase activation, contribute to malignant progression. Furthermore, emerging evidence links RAS mutations to brain metastases, highlighting their significance in CNS oncology. We also discuss recent clinical trials investigating RAS-targeted therapies, including covalent inhibitors, MEK inhibitors, and novel combination approaches. Given the increasing recognition of RAS pathway alterations in CNS malignancies, further research is needed to elucidate their role in tumor biology and explore targeted therapeutic interventions. Full article

Background/Objectives: Ovarian cancer remains one of the most commonly diagnosed malignancies among women worldwide. The heterogeneity among tumor subtypes and the emergence of treatment resistance have raised significant concerns regarding the long-term efficacy of chemotherapy, radiotherapy, and immunotherapy. In response to these challenges, drug repurposing strategies—utilizing existing drugs in novel therapeutic contexts—have gained increasing attention. This study aimed to investigate the cytotoxic and apoptotic effects of the combined application of doxorubicin (DX) and thymoquinone (TQ) on ovarian adenocarcinoma cells (OVCAR3). Methods: OVCAR3 cells were cultured in RPMI medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin. Cell viability and proliferation were assessed using the MTT assay following treatment with various concentrations of DX and TQ. NucBlue immunofluorescence staining was employed to examine nuclear morphology and to identify apoptosis-associated changes. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was per-formed to evaluate the expression levels of apoptosis-related and oncogenic pathway genes, including RAF, RAS, Bcl-2, and Bax. Results: The results demonstrated that the combination of DX and TQ significantly reduced OVCAR3 cell viability and induced apoptosis in a dose-dependent manner. qRT-PCR analysis revealed a downregulation of RAS, RAF, and Bcl-2 expression, along with an upregulation of Bax, indicating activation of the intrinsic apoptotic pathway. These findings suggest that thymoquinone exerts an-ti-proliferative and pro-apoptotic effects by modulating the RAS/RAF signaling cascade. Furthermore, the co-administration of thymoquinone with doxorubicin potentiated these effects, suggesting a synergistic interaction between the two agents. Conclusions: Histopathological and molecular evaluations further confirmed the activation of apoptosis and the suppression of key oncogenic pathways. Collectively, these results underscore the therapeutic potential of thymoquinone as both a monotherapy and an adjuvant to conventional chemotherapy, warranting further validation in preclinical and clinical studies. Full article

RAS mutations occur in about 30% of human cancers, leading to enhanced RAS signaling and tumor growth. KRAS is the most commonly mutated oncogene in human tumors, especially lung, pancreatic, and colorectal cancers. Direct targeting of KRAS is difficult due to its highly conserved sequence; but, its complex with the guanine nucleotide exchange factor Son of Sevenless (SOS) 1 promises an attractive target for inhibiting RAS-mediated signaling. Here, we first revealed putative allosteric binding sites of the SOS1, KRASG12C-SOS1 complex, and the ternary KRASG13D-SOS1 complex structures using two network-based models, the essential site scanning analysis and the residue interaction network model. The results enabled us to identify two new putative allosteric pockets for the ternary KRASG13D-SOS1 complex. These were then screened together with the known ligand binding site against the natural compounds in the InterBioScreen (IBS) database using the Glide software package developed by Schrödinger, Inc. The docking poses of seven hit compounds were assessed using 400 ns long molecular dynamics (MD) simulations with two independent replicas using Desmond, coupled with thermal MM-GBSA calculations for the estimation of the binding free energy values. The structural skeleton of the seven proposed compounds consists of different functional groups and heterocyclic rings that possess anti-cancer activity and exhibit persistent interactions with key residues in binding pockets throughout the MD simulations. STOCK1N-09823 was determined as the most promising hit that promoted the disruption of the interactions R73 (chain A)/N879 and R73 (chain A)/Y884, which are key for SOS1-mediated KRAS activation. Full article

Gliomas are a type of highly heterogeneous and invasive central nervous system tumor. Traditional treatment methods have limited efficacy, and the prognosis for patients remains poor. Recent studies have revealed the crucial roles of several abnormal signaling pathways in the pathogenesis of gliomas, including the Receptor Tyrosine Kinase/Rat Sarcoma Virus Oncogene/Phosphatidylinositol-3-Kinase (RTK/RAS/PI3K) pathway, the Wingless-Related Integration Site/β-Catenin (Wnt/β-Catenin) pathway, the Hippo/YAP (Hippo/Yes-associated protein) pathway, and the Slit/Robo (Slit Guidance Ligands/Roundabout) signaling pathway. These pathways play extremely vital roles in tumor proliferation, invasion, and treatment resistance. This article comprehensively and systematically reviews the molecular mechanisms of these signaling pathways, deeply summarizing the research progress of various treatment strategies, including targeted inhibitors, gene therapy, and nanomedicine against them. Moreover, the combination of targeted therapy and personalized treatment regimens is expected to overcome the current treatment bottleneck and provide a more favorable survival prognosis for glioblastoma patients. Full article

Cancer, characterized by the uncontrolled proliferation of cells, is one of the leading causes of death globally, with approximately one in five people developing the disease in their lifetime. While many driver genes were identified decades ago, and most cancers can be classified based on morphology and progression, there is still a significant gap in knowledge about genetic aberrations and nuclear DNA damage. The study of two critical groups of genes—tumor suppressors, which inhibit proliferation and promote apoptosis, and oncogenes, which regulate proliferation and survival—can help to understand the genomic causes behind tumorigenesis, leading to more personalized approaches to diagnosis and treatment. Aberration of tumor suppressors, which undergo two-hit and loss-of-function mutations, and oncogenes, activated forms of proto-oncogenes that experience one-hit and gain-of-function mutations, are responsible for the dysregulation of key signaling pathways that regulate cell division, such as p53, Rb, Ras/Raf/ERK/MAPK, PI3K/AKT, and Wnt/β-catenin. Modern breakthroughs in genomics research, like next-generation sequencing, have provided efficient strategies for mapping unique genomic changes that contribute to tumor heterogeneity. Novel therapeutic approaches have enabled personalized medicine, helping address genetic variability in tumor suppressors and oncogenes. This comprehensive review examines the molecular mechanisms behind tumor-suppressor genes and oncogenes, the key signaling pathways they regulate, epigenetic modifications, tumor heterogeneity, and the drug resistance mechanisms that drive carcinogenesis. Moreover, the review explores the clinical application of sequencing techniques, multiomics, diagnostic procedures, pharmacogenomics, and personalized treatment and prevention options, discussing future directions for emerging technologies. Full article

Vemurafenib is a BRAF (rapidly accelerated fibrosarcoma B-type)-targeted therapy used to treat patients with advanced, unresectable melanoma. It inhibits the MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) pathway and tumor proliferation in BRAF^V600E-mutated melanoma cells. Resistance to vemurafenib has been reported in melanoma patients due to secondary NRAS (neuroblastoma RAS viral oncogene homolog) mutations, which lead to paradoxical MAPK pathway activation and tumor proliferation. However, the impact of this paradoxical activation on mitochondrial dynamics and function in NRAS-mutated melanoma is unclear. Here, we investigated the effects of vemurafenib on NRAS^Q61R-mutated melanoma cells, focusing on mitochondrial dynamics and function. As expected, vemurafenib did not exhibit cytotoxicity in SK-MEL-147 NRAS^Q61R-mutated melanoma cells, even after 72 h of incubation. However, it significantly enhanced the MAPK/ERK signaling through paradoxical activation, accompanied by decreased expression of mitochondrial fusion proteins and activation of the fission protein DRP1 (dynamin-related protein 1), leading to small, rounded mitochondrial morphology. These observations were corroborated by transcriptome data obtained from NRAS-mutated melanoma patients, showing MFN1 (mitofusin 1) and OPA1 (optic atrophy 1) downregulation and DNM1L (DRP1 gene) upregulation. Interestingly, inhibition of mitochondrial fission with mdivi-1 or modulation of oxidative phosphorylation via respiratory chain inhibition or uncoupling significantly sensitized NRAS^Q61R-mutated melanoma cells to vemurafenib. Despite vemurafenib’s low cytotoxicity in NRAS-mutated melanoma, targeting mitochondrial dynamics and/or oxidative phosphorylation may offer a promising strategy for combined therapy. Full article

Objective: Rat sarcoma (Ras) proteins, Kirsten, Harvey, and Neuroblastoma rat sarcoma viral oncogene homolog (KRAS, HRAS, and NRAS, respectively), are a family of GTPases, which are key regulators of cellular growth, differentiation, and apoptosis through signal transduction pathways modulated by growth factors that have been recognized to be dysregulated in PCOS. This study explores Ras signaling proteins and growth factor-related proteins in polycystic ovary syndrome (PCOS). Methods: In a well-validated PCOS database of 147 PCOS and 97 control women, plasma was batch analyzed using Somascan proteomic analysis for circulating KRas, Ras GTPase-activating protein-1 (RASA1), and 45 growth factor-related proteins. The cohort was subsequently stratified for BMI (body mass index), testosterone, and insulin resistance (HOMA-IR) for subset analysis. Results: Circulating KRas, and RASA1 did not differ between PCOS and control women (p > 0.05). EGF1, EGFR, and EGFRvIII were decreased in PCOS (p = 0.04, p = 0.04 and p < 0.001, respectively). FGF8, FGF9, and FGF17 were increased in PCOS (p = 0.02, p = 0.03 and p = 0.04, respectively), and FGFR1 was decreased in PCOS (p < 0.001). VEGF-D (p < 0.001), IGF1 (p < 0.001), IGF-1sR (p = 0.02), and PDGFRA (p < 0.001) were decreased in PCOS compared to controls. After stratifying for BMI ≤ 29.9 kg/m², EGFR FGF8, FGFR1 VEGF-D, IGF1, and IGF-1sR differed (p < 0.05) though EGF1, EGFRvIII, FGF8, FGFR1, and VEGF-D no longer differed; after subsequently stratifying for HOMA-IR, only FGFR1, VEGF-D, IGF1, and IGF-1sR differed between groups (p < 0.05). Conclusions: Several growth factors that activate Ras differ between women with and without PCOS, and when stratified for BMI and HOMA-IR, only FGFR1, VEGF-D, IGF1, and IGF-1sR differed; these appear to be inherent features of the pathophysiology of PCOS. Full article

The epidermal growth factor receptor (EGFR) regulates gene expression through two primary mechanisms: as a growth factor in the nucleus, where it translocates upon binding its ligand, or via its intrinsic tyrosine kinase activity in the cytosol, where it modulates key signaling pathways such as RAS/MYC, PI3K, PLCγ, and STAT3. During tumorigenesis, these pathways become deregulated, leading to uncontrolled proliferation, enhanced migratory and metastatic capabilities, evasion of programmed cell death, and resistance to chemotherapy or radiotherapy. The RAS and MYC oncogenes are pivotal in tumorigenesis, driving processes such as resistance to apoptosis, replicative immortality, cellular invasion and metastasis, and metabolic reprogramming. These oncogenes are subject to regulation by a range of epigenetic and post-transcriptional modifications. This review focuses on the deregulation of EGFR, RAS, and MYC expression caused by (epi)genetic alterations and post-translational modifications. It also explores the therapeutic potential of targeting these regulatory proteins, emphasizing the importance of phenotyping neoplastic tissues to inform the treatment of cancer. Full article

Background: Dysregulation of receptor tyrosine kinase c-MET is known to promote tumor development by stimulating oncogenic signaling pathways in different cancers, including pediatric neuroblastoma (NB). NB is an extracranial solid pediatric cancer that accounts for almost 15% of all pediatric cancer-related deaths, with less than a 50% long-term survival rate. Results: In this study, we analyzed a large cohort of primary NB patient data and revealed that high MET expression strongly correlates with poor overall survival, disease progression, relapse, and high MYCN levels in NB patients. To determine the effects of c-MET in NB, we repurposed a small molecule inhibitor, tivantinib, and found that c-MET inhibition significantly inhibits NB cellular growth. Tivantinib significantly blocks NB cell proliferation and 3D spheroid tumor formation and growth in different MYCN-amplified and MYCN-non-amplified NB cell lines. Furthermore, tivantinib blocks the cell cycle at the G2/M phase transition and induces apoptosis in different NB cell lines. As expected, c-MET inhibition by tivantinib inhibits the expression of multiple genes in PI3K, STAT, and Ras cell signaling pathways. Conclusions: Overall, our data indicate that c-MET directly regulates NB growth and 3D spheroid growth, and c-MET inhibition by tivantinib may be an effective therapeutic approach for high-risk NB. Further developing c-MET targeted therapeutic approaches and combining them with current therapies may pave the way for effectively translating novel therapies for NB and other c-MET-driven cancers. Full article

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is associated with high morbidity and mortality. One of the main challenges in the management of HCC is late clinical presentation and thus diagnosis of the disease, which results in poor survival. The pathogenesis of HCC is complex and involves chronic liver injury and genetic alterations. Diagnosis of HCC can be made either by biopsy or imaging; however, conventional tissue-based biopsy methods and serological biomarkers such as AFP have limited clinical applications. While hepatocellular carcinoma is associated with a range of molecular alterations, including the activation of oncogenic signaling pathways, such as Wnt-TGFβ, PI3K-AKT-mTOR, RAS-MAPK, MET, IGF, and Wnt-β-catenin and TP53 and TERT promoter mutations, microfluidic applications have been limited. Early diagnosis is crucial for advancing treatments that would address the heterogeneity of HCC. In this context, microfluidic droplet-based methods are crucial, as they enable comprehensive analysis of the genome and transcriptome of individual cells. Single-cell RNA sequencing (scRNA-seq) allows the examination of individual cell transcriptomes, identifying their heterogeneity and cellular evolutionary relationships. Other microfluidic methods, such as Drop-seq, InDrop, and ATAC-seq, are also employed for single-cell analysis. Here, we examine and compare these microfluidic droplet-based methods, exploring their advantages and limitations in liver cancer research. These technologies provide new opportunities to understand liver cancer biology, diagnosis, treatment, and prognosis, contributing to scientific efforts in combating this challenging disease. Full article