Enhancer and metabolic rewiring by KMT2C–COMPASS or KMT2D–COMPASS family loss in cancer creates druggable vulnerabilities

A new review published in Nature Reviews Cancer examines how loss-of-function mutations in the KMT2C or KMT2D components of the COMPASS chromatin-modifying complex drive cancer progression through enhancer and metabolic rewiring. The authors, Zhao and Shilatifard, systematically catalog the druggable vulnerabilities that emerge from altered COMPASS activity, spanning epigenetic, metabolic, immune, and DNA repair pathways. These findings provide a roadmap for therapeutic strategies targeting cancers harboring COMPASS mutations, which are among the most frequently mutated epigenetic regulators across multiple tumor types. The review synthesizes growing evidence that COMPASS-deficient tumors may respond to specific combination therapies exploiting their acquired dependencies.