Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors.

ABSTRACT: MYC is a key driver in many aggressive and therapy-resistant cancers. We have developed and characterized a small-molecule MYC inhibitor named MYCi975. To uncover combination strategies for MYC inhibitors, we conducted a genome-wide CRISPR screen using MYCi975. This screen revealed a notable synthetic lethality when MYC inhibition was paired with disruption of mitochondrial complex I components, but not other complexes. Mechanistically, MYC inhibition reduced oxidative phosphorylation and glycolysis, triggering a compensatory up-regulation of complex I genes. Consequently, genetic or pharmacological targeting of complex I sensitized tumors to MYCi975 treatment, leading to increased purine catabolism and infiltration of CD8⁺ T cells and macrophages into tumors. Additionally, a wi

SUBMITTER: Yang W 

PROVIDER: S-EPMC12266110 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature