MYC proto-oncogene (MYC)

Overview

MYC (c-Myc) is a nuclear phosphoprotein that acts as a sequence-specific transcription factor and ranks among the most frequently deregulated oncoproteins in human cancer. It belongs to the basic helix-loop-helix leucine-zipper (bHLH-LZ) class of DNA-binding proteins and is the product of the MYC proto-oncogene on chromosome 8q24. On its own MYC has little transcriptional activity; it must heterodimerize with its obligate partner MAX to bind E-box motifs at target promoters and enhancers, where it recruits coactivator and chromatin-modifying complexes. Through this activity MYC drives broad programs of cell growth and proliferation — ribosome biogenesis, nucleotide and glycolytic metabolism, and cell-cycle entry via effectors such as cyclin-dependent kinase 1 (CDK1). The protein is short-lived and tightly regulated post-translationally: phosphorylation at Ser62 and Thr58, the latter dependent on glycogen synthase kinase 3β (GSK-3β), primes MYC for ubiquitin-mediated proteasomal degradation, so that its abundance normally tracks mitogenic signaling rather than persisting.

In malignancy this control is lost through gene amplification, chromosomal translocation, protein stabilization, or sustained upstream signaling from pathways such as MAPK, PI3K/Akt, Wnt/β-catenin, NF-κB, and CD44/JAK2/STAT3. Elevated MYC is documented across leukemias, colorectal cancer, hepatocellular carcinoma, nasopharyngeal carcinoma, tongue and other head-and-neck squamous cell carcinomas, and lung adenocarcinoma, frequently alongside lesions in KRAS, BRAF, or CDH1 and with downstream effects on apoptotic regulators such as B-cell lymphoma 2 (Bcl-2). MYC can also repress a subset of targets — for example, it restrains tumor-associated calcium signal transducer 2 (TACSTD2/TROP2), so that MAPK-pathway inhibition by EGFR tyrosine kinase inhibitors like osimertinib lowers MYC and derepresses TROP2 in drug-tolerant persister cells, a dependency that TROP2-directed antibody–drug conjugates can exploit. Because its largely intrinsically disordered surface offers few conventional binding pockets, MYC has long been regarded as difficult to drug directly, and most therapeutic effort targets it indirectly — through upstream kinases and signaling nodes, transcriptional cofactor and super-enhancer dependencies, or regulators of MYC protein stability. Its influence extends beyond classical oncology, with MYC-linked transcriptional and apoptotic programs implicated in tissue injury settings such as spinal cord injury and ischemia-reperfusion-driven acute kidney injury.

Recent Publications Summary

Recent studies have explored diverse therapeutic strategies targeting MYC proto-oncogene (MYC) across multiple cancer types. Direct MYC degradation has been achieved through novel molecular approaches: a ribonuclease-targeting chimera (RiboTAC) designed to promote MYC mRNA degradation showed potent anti-multiple myeloma activity in patient samples and xenograft models 42526890Jul, while small-molecule inhibitors of RUVBL1/2, essential cofactors of MYC, demonstrated improved efficacy in MYC-dependent Burkitt lymphoma xenografts 42017951Apr. Protein stabilization mechanisms controlling MYC have been implicated in therapeutic resistance; USP15 deubiquitinase was found to stabilize c-MYC in renal cell carcinoma, driving sunitinib resistance through metabolic reprogramming, while USP15 depletion restored drug sensitivity 42054210Apr. WEE1 kinase similarly stabilizes MYC protein through a cytoplasmic mechanism in esophageal adenocarcinoma, and WEE1 inhibition reduced MYC levels and overcame drug resistance 41812823Mar.

MYC transcriptional activity has been targeted through epigenetic and small-molecule approaches in multiple malignancies. Panobinostat, a pan-histone deacetylase inhibitor, suppressed MYC expression in nasopharyngeal carcinoma and reduced transcription of homologous recombination genes 42331772Jun. Kojic acid inhibited melanoma progression by impairing MYC-driven transcriptional programs, specifically suppressing CCNA2 and KPNA2, genes associated with poor prognosis 41690656Feb. In acute myeloid leukemia, MO-IPS, a potent MYC-PRMT inhibitor, suppressed tumor growth and at optimized doses synergized with anti-PD-1 therapy by enhancing CD8+ T cell infiltration and reducing regulatory T cell accumulation 42307804Jun. The c-Myc inhibitor JQ1 was incorporated into a ROS-sensitive hydrogel that suppressed glycolysis in tumor cells while promoting CAR-T cell infiltration in postoperative tumor microenvironments 42105866May.

G-quadruplex stabilization at MYC promoter regions has emerged as a distinct therapeutic approach. PARP inhibitor VIII exhibited marked affinity for the c-myc G-quadruplex motif with preference over duplex DNA 42281329Jun, while tris-aryl imidazole analogs were developed as bifunctional ligands targeting both c-Myc and KRAS G-quadruplexes; the lead compound HZ-1 induced ferroptosis and immunogenic cell death in breast cancer models and suppressed tumor growth in vivo 41719920Feb.

MYC regulation has been identified as a central node in multiple cancer networks and therapeutic mechanisms. In hepatocellular carcinoma associated with psychological stress, the metabolite taurocholate stabilized CBX5, which cooperated with MYC to activate PHGDH transcription and reduced ferroptotic sensitivity; ursodeoxycholic acid suppressed tumor growth in stress-associated models 42435771Jul. In non-small-cell lung cancer, c-Myc acts as a transcriptional repressor of TROP2; TKI-mediated reduction in c-Myc levels upregulates TROP2 in drug-tolerant persister cells, and combining TROP2-targeting antibody-drug conjugates with EGFR-TKIs effectively suppressed persister emergence and delayed tumor relapse 42314664Jun. In pancreatic ductal adenocarcinoma, tumor Treating Fields therapy suppressed c-Myc expression and induced immunogenic cell death, with enhanced efficacy in combination with gemcitabine and nab-paclitaxel 41760592Feb. CRISPR activation screening revealed tissue-specific selection for Myc activation during lung and pancreatic cancer initiation, with strong selection for Myc in pancreatic tumors generating immune-cold microenvironments 41999750Apr. Enhanced MYC transcriptional activity was observed in high-risk proteogenotypes of diffuse large B-cell lymphoma independent of MYC translocations 42242231Jun.

What Changes, What Holds

1. MYC can now be attacked through its RNA and cofactor dependencies, and resistance can arise from MYC-stabilizing enzymes
NEW DIRECTION RiboTAC-mediated MYC mRNA degradation and RUVBL1/2 inhibition extend the therapeutic map beyond the long-standing focus on upstream signaling and protein stability, showing that MYC can be suppressed at the transcript level or by disabling essential cofactors 42526890Jul42017951Apr. The same paragraph also strengthens the case that MYC abundance is a resistance node, because USP15 and WEE1 both preserve c-MYC in settings where that sustains sunitinib or other drug resistance 42054210Apr41812823Mar.

2. MYC remains a central transcriptional target, but these studies broaden the ways it can be suppressed and linked to immunity
REINFORCES Panobinostat, kojic acid, MO-IPS, and JQ1-based delivery all fit the established view that MYC-driven transcriptional programs are therapeutically vulnerable, rather than overturning it 42331772Jun41690656Feb42307804Jun42105866May. What is new is the breadth of downstream consequences: homologous recombination, glycolysis, and the tumor immune milieu all appear coupled to MYC inhibition, including improved CD8+ infiltration and CAR-T access.

3. Stabilizing MYC promoter G-quadruplexes adds a direct DNA-structure route to MYC suppression
NEW DIRECTION PARP inhibitor VIII and the tris-aryl imidazole series shift attention from MYC protein or upstream signaling to the promoter architecture itself, exploiting c-myc G-quadruplexes as druggable elements 42281329Jun41719920Feb. That does not contradict the baseline, but it does expand the therapeutic logic: MYC can be constrained by locking its transcriptional template into a nonproductive structure, with one lead also linking this strategy to ferroptosis and immunogenic cell death.

4. MYC is emerging as a context-specific node that can drive resistance, immune escape, and stress-adapted metabolism
NEW DIRECTION The established account already places MYC in broad oncogenic transcription, but these studies add several settings in which MYC acts as a local organizer of tumor adaptation: stress-associated hepatocellular carcinoma, TROP2 derepression in drug-tolerant lung cancer cells, pancreatic responses to tumor Treating Fields, and immune-cold initiation programs 42435771Jul42314664Jun41760592Feb41999750Apr. The lymphoma finding also suggests that high MYC activity can matter even without translocation, complicating genotype-based assumptions.

Overview update candidates: MYC RNA degradation; RUVBL1/2 cofactor targeting; USP15/WEE1-mediated stabilization in resistance; MYC-linked epigenetic suppression with immune-modulating effects; MYC promoter G-quadruplex targeting; MYC in stress-associated ferroptosis resistance; TROP2 repression in persisters; therapy-induced immunogenic cell death; translocation-independent MYC activation.