MYC

Overview

MYC (also known as c-Myc or proto-oncogene c-Myc) is a multifunctional nuclear transcription factor encoded by the MYC gene on chromosome 8q24 and is one of the most frequently dysregulated oncoproteins in human cancer. As a member of the basic helix-loop-helix leucine zipper (bHLH-LZ) family, MYC heterodimerizes with its obligate partner MAX to bind canonical E-box sequences (CACGTG) in the promoters of target genes, thereby driving transcriptional programs that control cell proliferation, growth, differentiation, metabolism, and apoptosis. Under normal physiological conditions, MYC expression is tightly regulated and transient, responding to mitogenic signals; however, in malignancy, MYC is constitutively overexpressed through gene amplification, chromosomal translocation, upstream pathway activation (e.g., Wnt/β-catenin pathway, PI3K/Akt signaling pathway, MAPK), or impaired proteolytic degradation. MYC protein stability is regulated by phosphorylation at key residues (Ser62 and Thr58) and by the ubiquitin-proteasome system, with deubiquitinases and E3 ligases acting as critical gatekeepers of its half-life.

The biological reach of MYC is exceptionally broad: it directly or indirectly controls an estimated 15% of all human genes, orchestrating ribosome biogenesis, nucleotide synthesis, glycolysis, glutamine metabolism, and cell cycle entry. Its deregulation is documented across a vast spectrum of malignancies — including lymphomas, leukemias, sarcomas, lung adenocarcinoma, and pancreatic cancer — making it one of the most compelling yet historically challenging targets in oncology. Recent advances in understanding MYC's indirect targetability, its dependencies on cofactor complexes, and the regulatory role of G-quadruplex (G4) DNA structures in its promoter have reinvigorated therapeutic strategies.

Focus of Latest Publications

Recent publications have continued to position MYC as a central oncogenic node across diverse tumor types, with multiple studies focusing on how MYC activity can be modulated therapeutically or used to define tumor dependencies. In MYC-driven lung adenocarcinoma, targeting AURKB was investigated as a way to disrupt MYC-mediated oncogenic programs and attenuate tumor growth. Similarly, a live-cell single-molecule tracking platform was used to identify a potent RUVBL1/2 inhibitor, building on evidence that the RUVBL1/2 complex is an essential cofactor of MYC and that inhibition can reduce c-MYC levels in vitro; the optimized compound showed improved efficacy in a MYC-dependent Burkitt lymphoma xenograft model. In esophageal adenocarcinoma, WEE1 was shown to stabilize MYC and promote therapeutic resistance, and WEE1 inhibition reduced MYC protein levels and transcriptional activity while enhancing response to combination treatment with Panobinostat.

Several studies examined MYC regulation through protein stability, transcriptional control, or upstream signaling. In clear cell renal cell carcinoma, USP15 stabilized c-Myc by K48-linked deubiquitination, thereby promoting sunitinib resistance through repression of cuproptosis-related pathways; conversely, MYCBP2 promoted c-Myc degradation. In anaplastic thyroid carcinoma, the NAT10/c-Myc positive feedback loop was reported to orchestrate tRNA ac4C modification and OTUB1-mediated protein stabilization, linking MYC to tumor progression. In pediatric acute myeloid leukemia, raloxifene was identified through virtual screening as a small-molecule inhibitor targeting ANP32B, with the study specifically noting regulation of C-MYC expression. In melanoma, kojic acid inhibited progression by disrupting MYC-driven transcriptional programs without altering MYC expression, but impairing MYC promoter binding and downstream activation of CCNA2 and KPNA2.

Other recent work explored MYC as a transcriptional target or a promoter-associated therapeutic vulnerability. PARP inhibitor VIII was found to bind and stabilize the c-myc G-quadruplex more strongly than PARP inhibitor XI, suggesting dual activity against PARP and oncogenic G-quadruplex structures. Small-sized tris-aryl imidazoles were also developed as bifunctional ligands for c-Myc and Kras G-quadruplexes, with one lead compound showing antitumor activity in breast cancer models. In pancreatic cancer, in vivo CRISPR activation screening revealed strong selection for Myc activation in autochthonous tumors, including an immune-cold phenotype in the pancreas. In pancreatic ductal adenocarcinoma models, Tumor Treating Fields significantly suppressed c-Myc expression and induced immunogenic cell death, although causality between c-Myc modulation and immune readouts was not established. In tongue squamous cell carcinoma cell lines derived from non-smokers, c-Myc expression was observed only in fibroblast-enriched cultures and not in the epithelial tumor cell lines, underscoring the importance of tumor microenvironment context in MYC-related analyses.