Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors

  • Sci Adv. 2025 Jul 18;11(29):eadw5228. doi: 10.1126/sciadv.adw5228.
William Yang  1  2 ,  Qianyu Guo  1  2 ,  Songhua Quan  1  2 ,  Zachary R Chalmers  1  2 ,  J Brandon Parker  3 ,  Mihai Truica  1  2 ,  Mary F Dufficy  1  2 ,  Megan M Kerber  1  2 ,  Karthik Vasan  2  4 ,  Dikshat G Gupta  1  2 ,  Adam W T Steffeck  1  2 ,  Hao Pan  1  2 ,  Mohammed Siddiqui  1  2 ,  H Tran Pham  5 ,  Gary E Schiltz  6 ,  Debabrata Chakravarti  2  3  7 ,  Navdeep S Chandel  2  4 ,  Sarki A Abdulkadir  1  2
Affiliations
  • 1. Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 2. The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 3. Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 4. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 5. Division of Internal Medicine, Weiss Memorial Hospital, Chicago, IL, USA.
  • 6. Department of Chemistry, Northwestern University, Evanston, IL, USA.
  • 7. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
PMID: 40668928 DOI: 10.1126/sciadv.adw5228
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 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.

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