The transcription factor MYC has moved to the forefront of melanoma research as a potential therapeutic target, according to a new review published in Frontiers.

The review consolidates evidence that MYC, a master regulator of cell growth and proliferation, is functionally critical to melanoma biology — even as the field has struggled for decades to drug it directly.

Why MYC matters in melanoma

MYC belongs to a family of transcription factors that control the expression of a large fraction of the genome. In many cancers, amplification or overexpression of MYC drives unchecked proliferation, metabolic reprogramming, and resistance to apoptosis. In melanoma, MYC activity is frequently elevated, and the review highlights its involvement in tumor progression and treatment resistance — a pressing clinical problem given that a substantial share of advanced melanoma patients fail to achieve durable responses to current standard-of-care options.

Checkpoint inhibitors and BRAF/MEK targeted therapies have transformed cutaneous melanoma management, but primary and acquired resistance limit long-term benefit for many patients. MYC's central position downstream of multiple oncogenic pathways — including MAPK signaling, the pathway activated in the majority of cutaneous melanomas bearing BRAF or NRAS mutations — positions it as a convergent node that tumors may struggle to bypass.

The druggability problem

Despite its appeal as a target, MYC has long been considered "undruggable." The protein lacks well-defined binding pockets, it acts intracellularly, and it functions through protein-protein interactions — notably with its obligate partner MAX — that are difficult to disrupt with conventional small molecules.

The review surveys strategies researchers have developed to work around these constraints. These include indirect approaches aimed at upstream regulators such as BRD4, targeted by BET inhibitors, and at synthetic lethal vulnerabilities created by MYC overexpression. Direct approaches have also advanced: stapleed peptides and mini-proteins designed to disrupt the MYC-MAX interaction, and omomyc-based candidates that act as dominant-negative inhibitors of MYC transcriptional activity.

Evidence and clinical outlook

The review draws on preclinical data across melanoma models demonstrating that MYC inhibition reduces proliferation and tumor fitness. Clinical translation remains at an early stage, with several MYC-directed strategies in earlier phases of development across oncology more broadly. The authors argue that melanoma, given its mutational landscape and reliance on MAPK-pathway signaling feeding into MYC, is a rational disease setting in which to prioritize these agents.

The piece also addresses combination logic: pairing MYC inhibition with existing immunotherapies or targeted therapies could, based on the reviewed evidence, overcome resistance mechanisms that currently limit their durability.

Bottom line

For dermatologists and oncology teams managing advanced cutaneous melanoma, the review frames MYC as one of the most consequential unresolved targets in the disease. Whether omomyc-like inhibitors, BET inhibitors, or synthetic lethal approaches translate into approved therapies will depend on trials now working their way through the pipeline — but the review's authors position MYC-directed therapy as a credible next frontier in melanoma treatment.