MYC-Dependent Signaling in Cancer Biology

MYC is a family of helix–loop–helix transcription factors that orchestrate fundamental cellular programmes including proliferation, metabolism, differentiation and apoptosis. In normal tissues, MYC expression is tightly regulated at the transcriptional, translational and post-translational levels, ensuring tissue homeostasis and controlled cell growth. Oncogenic deregulation of MYC occurs via gene amplification, chromosomal translocation, enhancer hijacking or aberrant signal transduction, leading to sustained MYC activity in a wide spectrum of human cancers. Elevated MYC drives a broad transcriptional reprogramming that enhances ribosome biogenesis, glycolysis, nucleotide synthesis and mitochondrial function, while suppressing differentiation and promoting survival. MYC exerts its effects by dimerising with MAX and recruiting co-factors to E-box sequences within target gene promoters, but it also engages multiple interactors that modulate its stability and chromatin association. The pervasive involvement of MYC in tumour initiation, progression and therapeutic resistance has spurred efforts to exploit synthetic lethal vulnerabilities and to develop direct or indirect inhibitors, transforming our understanding of oncogenic circuitry and offering avenues for targeted intervention.

Research from Nature Portfolio

Early clinical investigation of a novel MYC inhibitor miniprotein has demonstrated acceptable safety and preliminary antitumour activity in patients with advanced solid malignancies. Weekly intravenous administration in a classical dose-escalation design revealed manageable infusion-related reactions and pharmacokinetic properties characterised by a half-life of approximately 40 hours and tissue saturation at higher dose levels. Signs of disease stabilisation correlated with transcriptomic signatures of on-target engagement and suggested potential pharmacodynamic markers for patient stratification. Complementing these clinical findings, mechanistic studies in bladder cancer have uncovered a non-canonical role for DNA polymerase POLD1 in stabilising MYC. POLD1 binds the MYC homology box 1 domain, competing with the E3 ligase FBXW7 and thereby attenuating MYC ubiquitination and degradation. This POLD1–MYC complex enhances transcriptional activity and establishes a positive feedback loop that promotes proliferation and metastasis. These insights identify POLD1 as both a biomarker of MYC-driven malignancy and a candidate for therapeutic targeting.

MYC-Dependent Signaling in Cancer Biology publication trend

The graph below shows the total number of articles in myc-dependent signaling in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Oncogene: A gene that, when mutated or overexpressed, drives the transformation of normal cells into cancerous cells.

Transcription factor: A protein that binds DNA regulatory elements to control the rate of gene transcription.

Ubiquitination: A post-translational modification in which ubiquitin molecules are attached to a protein, often marking it for degradation.

Pharmacokinetics: The study of drug absorption, distribution, metabolism and excretion in the body.

Auxin-degron system: A tool for inducible protein degradation in cells or organisms, based on plant hormone-mediated recruitment of ubiquitin ligase.

Synthetic lethality: A genetic interaction where co-occurrence of two otherwise non-lethal alterations leads to cell death, exploitable in targeted therapy.

Pancreatic ductal adenocarcinoma (PDAC): The most common type of pancreatic cancer, originating from the ductal epithelium.

References

1. MYC targeting by OMO-103 in solid tumors: a phase 1 trial. Nature Medicine (2024).
2. Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2. Gut (2024).
3. DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC. Nature Communications (2023).