Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors
- William Yang
- Qianyu Guo
- Songhua Quan
- Zachary R. Chalmers
- J. Brandon Parker
- Mihai Truica
- Mary F. Dufficy
- Megan M. Kerber
- Karthik Vasan
- Dikshat G. Gupta
- Adam W. T. Steffeck
- Hao Pan
- Deepesh K. Padhan
- Maya A. Moran
- Mohammed Siddiqui
- H. Tran Pham
- Gary E. Schiltz
- Debabrata Chakravarti
- Navdeep S. Chandel
- Sarki A. Abdulkadir
2025-07-16
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 wide range of tumor cells with lower complex I expression showed increased MYC dependency. These results indicate that metabolic adaptation to MYC inhibition exposes a targetable weakness at complex I and provide a rational strategy for combination therapy with emerging MYC inhibitors.