Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors
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<sup>+</sup> 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.
Authors
- J. Brandon Parker (ORCID: https://orcid.org/0000-0002-9152-8913)
- Mark Kerber
- Adam W. T. Steffeck (ORCID: https://orcid.org/0000-0002-5660-9371)
- William Y. Yang
- Mihai I. Truica (ORCID: https://orcid.org/0000-0002-0866-1407)
- Dikshat Gopal Gupta (ORCID: https://orcid.org/0000-0002-9449-7585)
- Navdeep S. Chandel (ORCID: https://orcid.org/0000-0001-7208-3886)
- Debabrata Chakravarti (ORCID: https://orcid.org/0000-0001-8446-8599)
- Zachary R. Chalmers (ORCID: https://orcid.org/0000-0003-1012-8529)
- Karthik Vasan
- Sarki A. Abdulkadir (ORCID: https://orcid.org/0000-0003-2963-2899)
- Hao Pan (ORCID: https://orcid.org/0000-0002-5543-4792)
- Gary E. Schiltz (ORCID: https://orcid.org/0000-0003-4180-5051)
- Songhua Quan (ORCID: https://orcid.org/0009-0004-6474-6407)
- Mary F. Dufficy (ORCID: https://orcid.org/0009-0004-7761-6839)
- Qianyu Guo (ORCID: https://orcid.org/0009-0008-8840-6676)
- Mohammed Siddiqui (ORCID: https://orcid.org/0009-0002-3665-800X)
- Hoang Tran Pham (ORCID: https://orcid.org/0000-0001-5498-615X)
Institutions
- Northwestern University (US)
- Weiss Memorial Hospital (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1126/sciadv.adw5228
- Citations
- 2
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 1.61