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Cancer-Driving Molecules: From Molecular Mechanisms to Novel Therapeutics

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 29 January 2027 | Viewed by 9068

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Dr. Georgios Pantouris

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Department of Chemistry, University of the Pacific, Stockton, CA 95211, USA
Interests: structural biology; drug discovery; cancer biology; protein dynamics
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Dear Colleagues,

Insights into the tumor microenvironment have led to the development of targeted therapies that not only extend the lifespan of cancer patients but also improve their quality of life. In some cancers, targeted therapies have displaced standard-of-care treatment plans, whereas in others, cytotoxic and targeted therapies are used in combination to enhance efficacy and address tumor heterogeneity. The success of targeted therapies is supported by a comprehensive analysis of cancer-driving molecules, which are found in the tumor microenvironment. The structural and/or functional modification of such molecules has been shown to manipulate the immune system, promoting cancer cell survival and metastasis. Therefore, an in-depth characterization of these molecules could facilitate the discovery of next-generation therapeutics, further enhancing personalized treatment plans and expanding options for patients with advanced metastatic cancers.

This Special Issue entitled “Cancer-Driving Molecules: From Molecular Mechanisms to Novel Therapeutics” is open to original articles, short communications, case reports, and reviews from all the areas of cancer research. We welcome studies that provide insights into any type of oncogenic protein or protein complex, including but not limited to protein–protein, protein–ligand, protein–DNA, and protein–RNA interactions. Submissions focused on drug discovery at the preclinical stage, as well as studies utilizing checkpoint inhibitors or other mechanistic probes, are also encouraged. Examples of molecules within the scope of this Special Issue include CD receptors (e.g., CD19, CD40, CD47, CD74, and CD137), cytokines (e.g., MIF, D-DT, IFN-γ, TNF-α, and various interleukins), chemokines (e.g., CXCLs and CCLs), and chemokine receptors (e.g., CXCRs and CCRs). We also welcome studies on RNA- or DNA-binding proteins (e.g., YTHDF2 and BRCA1), cell death-related proteins (e.g., BCL2 and caspases), oncogenic enzymes (e.g., IDO, KRAS, NQO1, and IDH1), and ubiquitin-related proteins (e.g., E3 ligases). Checkpoint proteins (e.g., PD-1/PD-L1), transcription factors (e.g., STAT3 and MYC), kinases (e.g., ROS1 and NTRK1), members of the epidermal growth factor receptor (EGFR) family (e.g., HER1–4), bromodomain-containing proteins (e.g., BRD4), and many others are also of interest.

Dr. Georgios Pantouris
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

cancer
mechanism of action
tumor microenvironment
immune system
DNA/RNA/protein
small-molecule probes
activation/inhibition
biological activity

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Related Special Issue

Immunomodulatory Molecules in Cancer in International Journal of Molecular Sciences (9 articles)

Published Papers (8 papers)

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Research

Jump to: Review

14 pages, 2396 KB

Open AccessArticle

The Role of MNX1–AS1 in Ovarian Cancer Resistance and Tumor Progression via RNA–RNA Interactions

by Alvaro Gutierrez, Carolina Larronde, Salomé Silva, Constanza Castro, Rodrigo Maldonado, Daniela León, Juan Machuca, Carmen Gloria Ili, Priscilla Brebi, Kurt Buchegger and Tamara Viscarra

Int. J. Mol. Sci. 2026, 27(8), 3428; https://doi.org/10.3390/ijms27083428 - 11 Apr 2026

Viewed by 523

Abstract

Ovarian cancer (OC) remains one of the deadliest gynecological malignancies, largely due to late diagnosis and the emergence of resistance to platinum–based chemotherapy. Long non–coding RNAs (lncRNAs) have recently emerged as key regulators of tumor progression and therapeutic adaptation. In this study, we performed integrative transcriptomic profiling of patient–derived TCGA ovarian tumor samples and carboplatin–resistant A2780 (CBDCA–R–A2780) cells to identify lncRNAs whose dysregulation overlaps between a cell–line resistance model and patient tumors. Our analyses revealed extensive transcriptional remodeling across both datasets, with MNX1–AS1 consistently emerging as a strongly deregulated transcript. Differential expression analysis showed robust upregulation of MNX1–AS1 in resistant cells and tumor tissues, accompanied by correlations with epithelial–mesenchymal transition (EMT)–related transcription factors such as FOXA1 and SNAI2 and inverse associations with epithelial markers including CDH1. Computational predictions using RIblast identified specific MNX1–AS1 binding regions with candidate miRNAs and mRNAs, prioritizing EMT–related transcripts (e.g., SNAI2, FOXA1, ZEB1) with favorable hybridization energies for future validation. Additional prioritized interactors included genes linked to stress response (IER2, FOSB) and invasion (MMP11, MMP1). Because A2780 has been discussed as an endometrioid–like/non–serous ovarian cancer model, mechanistic inferences primarily apply to this in vitro context, while TCGA analyses provide associative support rather than mechanistic validation. Collectively, these findings highlight MNX1–AS1 as a candidate regulator associated with transcriptional reprogramming in OC and a promising prognostic biomarker warranting further functional testing. Full article

(This article belongs to the Special Issue Cancer-Driving Molecules: From Molecular Mechanisms to Novel Therapeutics)

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16 pages, 4615 KB

Open AccessArticle

S6K1 Modulates STAT3 Activation to Promote Resistance to Radiotherapy in Lung Cancer

by Ali Calderon-Aparicio, Noelle Francois, Tyler Grenda, Shan Xu, Olugbenga Okusanya, Jun He and Nicole L. Simone

Int. J. Mol. Sci. 2026, 27(4), 1915; https://doi.org/10.3390/ijms27041915 - 17 Feb 2026

Viewed by 702

Abstract

Radiotherapy is a mainstay in the management of locally advanced lung cancer; however, intrinsic and acquired radioresistance contribute to poor prognosis. S6K1, a serine/threonine kinase, regulates cell growth, protein synthesis, and survival, and is increased in tumors, which is linked to enhanced survival under therapeutic stress, including radiation. The mechanisms, however, are not fully understood. This study investigates the role of S6K1 in lung cancer radioresistance and the mechanisms involved. Intrinsic radioresistance in lung cancer cells was associated with increased S6K1 activation. Pharmacologic inhibition or genetic deletion of S6K1 enhanced radiosensitivity both in vitro and in vivo, highlighting the therapeutic potential of targeting S6K1. Transcriptomic analysis revealed that S6K1 deletion significantly downregulated STAT3 expression, a transcription factor that promotes radioresistance. S6K1 deletion reduced STAT3 phosphorylation and transcriptional activity, thereby sensitizing lung cancer to radiation. Additionally, radiation exposure or overexpression of a constitutively active S6K1 isoform restored STAT3 activation in S6K1 knockout cells, underscoring the regulatory role of S6K1 in STAT3 signaling. Together, these findings establish a novel S6K1–STAT3 axis that drives radioresistance in lung cancer and suggest that targeting this pathway may enhance radiotherapy efficacy. Full article

(This article belongs to the Special Issue Cancer-Driving Molecules: From Molecular Mechanisms to Novel Therapeutics)

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24 pages, 4161 KB

Open AccessArticle

Pmel17 Deficiency Affects Melanogenesis and Promotes Tumor Vascularization

by Justyna Sopel, Katarzyna Sarad, Anna Kozinska, Krystian Mokrzyński, Dariusz Szczygieł, Aleksandra Murzyn, Agnieszka Drzał, Andrzej Słomiński, Małgorzata Szczygieł and Martyna Elas

Int. J. Mol. Sci. 2026, 27(3), 1147; https://doi.org/10.3390/ijms27031147 - 23 Jan 2026

Viewed by 778

Abstract

Premelanosomal protein (Pmel, also known as Pmel17) is the major component of melanosomal fibrils and plays a key role in melanin polymerization, making it an important factor in melanogenesis. We investigated how the absence of Pmel affects the properties of B16F10 melanoma cells. Pmel-knockout B16F10 cells were generated using CRISPR/Cas9-mediated genome editing. A viability assay revealed no significant differences between wild-type (WT) and Pmel-knockout (KO) sublines; however, melanosome maturation was impaired. In Pmel KO cells, the cell cycle was disrupted, and higher levels of reactive oxygen species (ROS) were observed compared with WT cells. Moreover, the migration capacity and tube formation of melanoma cells were increased. Tumors derived from Pmel KO cells exhibited unchanged growth kinetics but reduced melanin content, along with enhanced vascularization and oxygenation. Thus, knockout of the Pmel17 gene in melanoma cells alters pigmentation, vascularization, and oxygenation of tumors. These parameters are crucial for both tumor progression and therapeutic response. Full article

(This article belongs to the Special Issue Cancer-Driving Molecules: From Molecular Mechanisms to Novel Therapeutics)

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32 pages, 3100 KB

Open AccessArticle

Network Controllability Reveals Key Mitigation Points for Tumor-Promoting Signaling in Tumor-Educated Platelets

by Özge Osmanoglu, Elif Özer, Shishir K. Gupta, Katrin G. Heinze, Harald Schulze and Thomas Dandekar

Int. J. Mol. Sci. 2025, 26(21), 10780; https://doi.org/10.3390/ijms262110780 - 5 Nov 2025

Viewed by 2165

Abstract

Therapeutic strategies targeting “tumor-educated platelets” (TEPs) and platelet–tumor interactions by key signaling pathways (ITAM, P2Y12) may reduce metastasis and cancer. Using a TEP gene expression dataset originally created to study swarm intelligence-enhanced detection of lung cancer cells (GSE89843), we did perform extensive transcriptome analysis to integrate these data with directed protein–protein interactions and build a TEP-specific signaling network. We analyze network topology and controllability and identify critical and indispensable nodes, as well as high-weight, usually high-score nodes. We reconstruct (pharmacological) controllable subnetworks of TEP signaling, which we then explore for drugs targets. We found 111 upregulated and 108 downregulated genes compared to control platelets, enriched in pathways related to extracellular matrix interactions, cytoskeleton organization, immune signaling, and platelet activation. Ribosomal function, apoptosis, and immune signaling were among the downregulated processes, highlighting unique TEP profiles in non-small-cell lung cancer (NSCLC). Our integrative analysis of TEPs in NSCLC reveals key transcriptional and network-based alterations harmful for the cancer patient. Using four complementary strategies, we identified five high-confidence genes (Gene symbols always given throughout the paper), ITGA2B, FLNA, GRB2, FCGR2A, and APP, as central to TEP signaling. These can be targeted by FDA-approved drugs. Fostamatinib, an SYK inhibitor, emerged as the top candidate drug to disrupt ITAM-mediated platelet activation selectively; metastasis-promoting metalloprotease and cytoskeletal targets influencing adhesion were also identified. A low-dose combination therapy of fostamatinib, Aducanumab, and acetylsalicylic acid (aspirin) may control TEP effects. In conclusion, our preclinical in silico approach revealed FDA-approved drugs that allow therapeutic targeting of metastasis-promoting TEPs and target NSCLC at the same time. Full article

(This article belongs to the Special Issue Cancer-Driving Molecules: From Molecular Mechanisms to Novel Therapeutics)

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28 pages, 3546 KB

Open AccessArticle

SCAMP3-Driven Regulation of ERK1/2 and Autophagy Phosphoproteomics Signatures in Triple-Negative Breast Cancer

by Beatriz M. Morales-Cabán, Yadira M. Cantres-Rosario, Eduardo L. Tosado-Rodríguez, Abiel Roche-Lima, Loyda M. Meléndez, Nawal M. Boukli and Ivette J. Suarez-Arroyo

Int. J. Mol. Sci. 2025, 26(19), 9577; https://doi.org/10.3390/ijms26199577 - 1 Oct 2025

Cited by 2 | Viewed by 1778

Abstract

Extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors show therapeutic potential in triple-negative breast cancer (TNBC), but resistance through compensatory signaling limits their efficacy. We previously identified the secretory carrier membrane protein 3 (SCAMP3) as a regulator of TNBC progression and ERK1/2 activation. Here, we investigated the role of SCAMP3 in ERK1/2 signaling and therapeutic response using TMT-based LC-MS/MS phosphoproteomics of wild-type (WT) and SCAMP3 knockout (SC3KO) SUM-149 cells under basal conditions, after epidermal growth factor (EGF) stimulation, and during ERK1/2 inhibition with MK-8353. A total of 4408 phosphosites were quantified, with 1093 significantly changed. SC3KO abolished residual ERK activity under MK-8353 and affected the compensatory activation of oncogenic pathways observed in WT cells. SC3KO reduced the phosphorylation of ERK feedback regulators RAF proto-oncogene serine/threonine-protein kinase Raf-1 (S43) and the dual-specificity mitogen-activated protein kinase kinase 2 (MEK2) (T394), affected other ERK targets, including nucleoporins, transcription factors, and metabolic enzymes triosephosphate isomerase (TPI1) (S21) and ATP-citrate lyase (ACLY) (S455). SCAMP3 loss also impaired the mammalian target of rapamycin complex I (mTORC1) signaling and disrupted autophagic flux, evidenced by elevated sequestosome-1 (SQSTM1/p62) and microtubule-associated protein light chain 3 (LC3B-II) with reduced levels of the autophagosome lysosome maturation marker, Rab7A. Beyond ERK substrates, SC3KO affected phosphorylation events mediated by other kinases. These findings position SCAMP3 as a central coordinator of ERK signaling and autophagy. Our results support SCAMP3 as a potential therapeutic target to enhance ERK1/2 inhibitor clinical efficacy and overcome adaptive resistance mechanisms in TNBC. Full article

(This article belongs to the Special Issue Cancer-Driving Molecules: From Molecular Mechanisms to Novel Therapeutics)

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Review

Jump to: Research

27 pages, 1046 KB

Open AccessReview

Circulating Dipeptides in Cancer: Degradation Fragments or Functional Metabolites?

by Kyung-Hee Kim and Byong Chul Yoo

Int. J. Mol. Sci. 2026, 27(10), 4438; https://doi.org/10.3390/ijms27104438 (registering DOI) - 15 May 2026

Abstract

Advances in mass spectrometry-based metabolomics have enabled the detection of numerous small molecules in biological systems, revealing complex metabolic alterations associated with cancer. Among these, dipeptides are consistently detected in plasma, serum, and tumor tissue metabolomic profiles, yet their biological significance is not fully understood. In most studies, circulating dipeptides are interpreted as nonspecific byproducts of protein degradation generated during increased proteolysis. However, accumulating evidence suggests that at least some endogenous dipeptides may have biological activities, including antioxidant effects, metabolic modulation, and potential signaling functions. In this review, we examine the possible origins, transport mechanisms, and biological implications of circulating dipeptides in cancer metabolomics. We discuss multiple sources of dipeptide generation, including intracellular proteolysis, autophagy, extracellular matrix remodeling, tumor cell death, host tissue catabolism, and microbiome metabolism. We also summarize current knowledge regarding peptide transport systems and intracellular dipeptide metabolism that may regulate the fate of these molecules within mammalian systems. In addition, evidence supporting the biological activities of certain endogenous dipeptides is reviewed to evaluate the possibility that some circulating dipeptides may function as bioactive metabolites. Finally, we propose conceptual frameworks for interpreting circulating dipeptides in cancer, including their potential roles as indicators of protein turnover, intermediates in amino acid recycling, stress-buffering molecules, metabolic signals, or components of tumor–host metabolic communication. A better understanding of circulating dipeptides may provide new insights into cancer metabolism and reveal previously overlooked metabolite classes with potential biomarker or functional significance. Full article

(This article belongs to the Special Issue Cancer-Driving Molecules: From Molecular Mechanisms to Novel Therapeutics)

14 pages, 1102 KB

Open AccessReview

CRISPR Interference to Inhibit Oncogenes for Cancer Therapy

by Bin Guo

Int. J. Mol. Sci. 2026, 27(8), 3564; https://doi.org/10.3390/ijms27083564 - 16 Apr 2026

Viewed by 796

Abstract

CRISPR interference (CRISPRi), a programmable transcriptional repression technology derived from nuclease-deficient CRISPR-Cas systems, has emerged as a powerful method for selectively inhibiting oncogene expression without altering the genomic DNA. This feature offers a major advantage over other oncogene targeting technologies such as CRISPR-mediated gene knockout, mRNA inhibition by siRNA or miRNA, or small-molecule inhibitors of the proteins encoded by the oncogenes, especially in cancers driven by transcriptional dysregulation or otherwise undruggable oncogenes. Here, I present a comprehensive review of CRISPRi mechanisms, delivery strategies, and preclinical applications in oncology (including advances in targeting core oncogenic drivers like MYC and KRAS). The advantages of CRISPRi as well as in vivo validation of CRISPRi-mediated tumor suppression are discussed. Finally, I outline translational challenges and future directions for incorporating CRISPRi into precision cancer therapies. The accumulated evidence suggests that CRISPRi could become a cornerstone for next-generation gene-regulatory therapeutics. Full article

(This article belongs to the Special Issue Cancer-Driving Molecules: From Molecular Mechanisms to Novel Therapeutics)

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21 pages, 1834 KB

Open AccessReview

Lineage Plasticity and Histologic Transformation in EGFR-TKI Resistant Lung Cancer

by Li Yieng Eunice Lau, Anders Jacobsen Skanderup and Aaron C. Tan

Int. J. Mol. Sci. 2026, 27(1), 445; https://doi.org/10.3390/ijms27010445 - 31 Dec 2025

Cited by 3 | Viewed by 1585

Abstract

Lineage plasticity, the ability of cancer cells to alter their differentiated state through transcriptional and epigenetic reprogramming, has emerged as a key mechanism of therapeutic resistance across cancers. This adaptive process can manifest in multiple ways, including epithelial–mesenchymal transition, acquisition of stem-like features, and histological transformation, the most striking and clinically apparent example. In EGFR-mutant lung adenocarcinoma (LUAD), lineage plasticity is increasingly recognized as a prevalent mechanism of acquired resistance to tyrosine kinase inhibitors (TKIs). Among its visible manifestations, histologic transformation into small-cell lung cancer (SCLC) is the most frequent, while squamous transformation and other phenotypic shifts also occur. Transformed tumors typically retain the initiating EGFR mutation but lose EGFR dependence, acquire neuroendocrine features, and display aggressive clinical behavior with poor clinical outcomes compared with both de novo SCLC and non-transformed LUAD. Recent studies show that plasticity arises through combined genomic, transcriptomic, and epigenetic reprogramming, often foreshadowed by molecular alterations before overt histological change. Spatial and single-cell profiling reveal heterogeneous trajectories and intermediate states, while functional models and multi-omics approaches have begun to identify therapeutic vulnerabilities distinct from both de novo EGFR-mutated SCLC and classical EGFR-mutated LUAD. Thus, lineage plasticity, whether manifested as histologic transformation or through more subtle epigenetic reprogramming, represents a formidable resistance mechanism in NSCLC. Defining its molecular basis and temporal dynamics will be essential for early detection, prognostication, and the development of tailored therapies. Full article

(This article belongs to the Special Issue Cancer-Driving Molecules: From Molecular Mechanisms to Novel Therapeutics)

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