Cracking MYC addiction: Synthetic-lethal vulnerabilities for precision cancer therapy

MYC-family activation (MYC, MYCN, and MYCL) is pervasive in human cancer and is strongly associated with aggressive biology and poor clinical outcomes. Although MYC remains challenging to inhibit directly, constitutive MYC activity imposes a high-demand cellular state that perturbs multiple interdependent cellular programs and homeostatic circuits, such as genome maintenance, gene expression, proteostasis, and metabolic homeostasis. To sustain viability under this burden, MYC-driven tumors become disproportionately dependent on nonredundant buffering pathways, creating exploitable synthetic-lethal vulnerabilities. In this review, we synthesize recent progress in mapping MYC synthetic lethal interactions using functional genomic screening, chemical and drug-repurposing approaches, and network-based computational modeling. We organize MYC-selective dependencies through a stress-buffer framework that links MYC-imposed pressures to druggable vulnerability classes and highlights targets with translational traction. We then translate this framework into an actionable roadmap for precision therapy, emphasizing functional measures of MYC activity beyond expression, context-aware stratification by lineage and co-alterations, and rational combination strategies designed to convert MYC-associated stress into tumor-selective killing while anticipating adaptive rewiring and resistance. Together, this perspective reframes MYC from an “undruggable” oncogene into a predictable vulnerability state that can be therapeutically exploited through biomarker-guided synthetic lethality.