c-Myc as a vulnerable target in cancer drug resistance.

The c-MYC proto-oncogene serves as a master regulator of cellular proliferation, metabolism, and apoptosis, playing a pivotal role in tumorigenesis and therapeutic resistance. Its ability to confer resistance to chemotherapy, targeted agents, and radiation across diverse malignancies presents a major clinical challenge. This comprehensive review systematically explores the molecular mechanisms through which c-MYC drives treatment resistance, including metabolic adaptation, enhanced DNA repair capacity, apoptotic blockade, cancer stem cell maintenance, and immune evasion. Key signaling pathways such as PI3K/AKT, Wnt/β-catenin, and HIF-1α are analyzed in the context of c-MYC -mediated resistance. Emerging evidence demonstrates how non-coding RNAs, epigenetic regulators, and post-translational modifications contribute to c-MYC stabilization and therapeutic failure. Current strategies to target c-MYC are evaluated, ranging from small-molecule inhibitors and BET bromodomain antagonists to rational combination therapies designed to overcome c-MYC-dependent survival pathways. By synthesizing recent advances and addressing the challenges posed by c-MYC's complex regulatory network, this analysis highlights the therapeutic promise of c-MYC inhibition. A deeper understanding of c-MYC's role in treatment resistance may yield innovative approaches to restore therapeutic sensitivity and improve patient outcomes in oncology.