Targeting MYC-Driven Cancers: From Oncogenic Addiction to Therapeutic Vulnerability

The MYC family oncoproteins, including MYC, MYCN, and MYCL, are potent drivers of tumorigenesis across a broad range of human cancers, frequently linked to aggressive tumor behavior, poor prognosis, and therapy resistance. They function as master transcriptional regulators that orchestrate gene expression programs governing nearly all aspects of tumor development. Despite their pivotal oncogenic role, they have long been considered "undruggable" due to their intrinsically disordered structure, lack of enzymatic activity, and the difficulty of targeting their protein-DNA and protein-protein interactions with conventional small-molecule approaches. Recent advances are beginning to overcome these challenges through innovative molecular strategies that either directly inhibit MYC activity or exploit MYC regulatory networks. Importantly, the first direct MYC inhibitor evaluated in humans, OMO-103, recently demonstrated promising antitumor activity in phase I clinical trials. Indirect approaches have focused on suppressing MYC transcription, translation, or stability by targeting upstream signaling pathways, as well as by exploiting MYC-associated cofactor interactions and synthetic lethal vulnerabilities to improve therapeutic specificity. In this review, we highlight the multifaceted roles of MYC in different cancer types and provide a comprehensive overview of current therapeutic strategies targeting MYC with a particular focus on epigenetic modifiers and metabolic vulnerabilities.