2. Academic Validation
  3. Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors

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

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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