This review synthesizes emerging insights into MYC orchestrated tumor microenvironment remodeling, reciprocal regulation with noncoding RNAs, and the transcriptional and epigenetic governance of metabolic reprogramming to posit MYC as a highly multidimensional regulatory node whose context‐dependent functions present both formidable challenges and promising new opportunities for effective therapeutic intervention.
Abstract
The MYC oncogene family constitutes a master regulatory hub in tumorigenesis, with functional complexity extending far beyond individual gene activities. Recent advances unveil cooperative yet context‐dependent antagonism and dynamic interplay among MYC family members, fundamentally reshaping our understanding of lineage specific oncogenic programs. This review synthesizes emerging insights into MYC orchestrated tumor microenvironment remodeling, reciprocal regulation with noncoding RNAs, and the transcriptional and epigenetic governance of metabolic reprogramming. We delineate mechanisms by which MYC drives therapeutic resistance and critically evaluate current strategies targeting MYC or its downstream networks, encompassing direct MYC–MAX disruptors, upstream pathway inhibitors, synthetic lethality, and combinatorial regimens with immune checkpoint blockade or conventional chemotherapy. We further discuss MYC's prognostic significance across diverse cancer types, the critical gap between preclinical efficacy and clinical outcomes, and emerging combination strategies aimed at overcoming acquired drug resistance. By integrating these rapidly evolving biological dimensions, we posit MYC as a highly multidimensional regulatory node whose context‐dependent functions present both formidable challenges and promising new opportunities for effective therapeutic intervention.
The MYC family oncoproteins, including MYC, MYCN, and MYCL, are potent drivers of tumorigenesis across a broad range of human cancers, frequently linked to aggressive tumor behavior, poor prognosis, and therapy resistance. They function as master transcriptional regulators that orchestrate gene expression programs governing nearly all aspects of tumor development. Despite their pivotal oncogenic role, they have long been considered “undruggable” due to their intrinsically disordered structure, lack of enzymatic activity, and the difficulty of targeting their protein–DNA and protein–protein interactions with conventional small-molecule approaches. Recent advances are beginning to overcome these challenges through innovative molecular strategies that either directly inhibit MYC activity or exploit MYC regulatory networks. Importantly, the first direct MYC inhibitor evaluated in humans, OMO-103, recently demonstrated promising antitumor activity in phase I clinical trials. Indirect approaches have focused on suppressing MYC transcription, translation, or stability by targeting upstream signaling pathways, as well as by exploiting MYC-associated cofactor interactions and synthetic lethal vulnerabilities to improve therapeutic specificity. In this review, we highlight the multifaceted roles of MYC in different cancer types and provide a comprehensive overview of current therapeutic strategies targeting MYC with a particular focus on epigenetic modifiers and metabolic vulnerabilities.
Lourdes Sainero-Alcolado, Dilraj Lama, Mohammad Alzrigat et al.· BioDrugs· 0 citations
A review summarizes the close link between Hippo-YAP1 dysregulation and drug resistance, and highlights intervention strategies with the potential to serve as novel treatment strategies.
Jiahui Zhao, Wanjie Zheng, Yan Zhang et al.· Critical reviews in oncology...· 0 citations
BACKGROUND
Cyclin-dependent kinase 9 (CDK9) is a central regulator of RNA polymerase II elongation and has emerged as a therapeutic target in tumors characterized by transcriptional addiction. Growing interest in selective inhibitors and targeted degraders has renewed attention to the translational potential of CDK9-directed therapy.
AREAS COVERED
This review summarizes the molecular functions of the CDK9/positive transcription elongation factor b (P-TEFb) axis, its role in super-enhancer-driven oncogenic programs, and the mechanisms by which CDK9 inhibition promotes apoptosis, epigenetic derepression, and tumor microenvironment remodeling. We also discuss representative small-molecule inhibitors and proteolysis-targeting chimera (PROTAC) degraders, emerging biomarkers for patient stratification, rational combination strategies, and the current landscape of resistance mechanisms.
EXPERT OPINION
Selective targeting of CDK9 offers a promising route for treating refractory malignancies, particularly when guided by transcriptional dependency, biomarker-informed dosing, and rational combination design. Future progress will likely depend on improving therapeutic index, refining translational biomarkers, and anticipating adaptive resistance during clinical development.
Ti-Yao Liu, Zhongran Liu, Wen-Jing Wei et al.· Expert opinion on therapeuti...· 0 citations
This review systematically consolidates recent advances in understanding how lncRNAs precisely modulate Notch pathway activity through diverse mechanisms, including acting as competing endogenous RNAs, direct protein binding, epigenetic regulation, and exosome-mediated intercellular communication.
Qing-Miao Shi, Na Lou, Huiwu Xing et al.· Frontiers in Cell and Develo...· 0 citations
This review delineates the molecular ontogeny of DNPC and advocates for the concept of "evolutionary interception," providing a strategic roadmap to dismantle the survival networks of advanced DNPC.
Lei Fan, Jia-Wei Li, Chun-Hao Mo et al.· Critical reviews in oncology...· 1 citation
Rational combination strategies are outlined that simultaneously target the RAS/MAPK axis and key TME vulnerabilities, such as immunotherapy combinations, CAF reprogramming, and ECM normalization, to overcome stromal-mediated resistance and achieve deeper, more sustained clinical responses.
Wen-Hao Ma, Xing-Yu Guo, Xiu-Ting Liu· Cancer Advances· 0 citations
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