Abstract LB318: MYC primes a paralog synthetic lethality involving the mitochondrial transporters TIMM17A and TIMM17B and N-acetylaspartate

Abstract To identify genes and pathways required for the survival of MYC-amplified cancers, we engineered and screened at genome scale an isogenic cell system where transformation is driven by oncogenic MYC. We found that the mitochondrial membrane transporter, TIMM17A, was uniquely essential for survival of MYC-transformed cells. This dependency arises due to MYC-driven suppression of TIMM17B, the paralog of TIMM17A. TIMM17A/B is an essential component of the mitochondrial TIM23 transporter complex, and MYC-induced suppression of TIMM17B creates a strong dependency on TIMM17A. N-acetylaspartate supplementation rescues TIMM17A dependency in MYC-amplified cell lines, highlighting the unique and crucial role of this metabolite in the viability of MYC-amplified cancers. These observations identify a paralog dependency required for the survival of a subset of MYC-driven cancers. Citation Format: Sydney M. Moyer, Nina Ilic, Sydney Gang, Jasmine Stavridi, Gaia Taig, Joseph D. DeAngelo, Andrea Jiang, Brian H. Shim, Jonathan P. Rennhack, Melis A. Akinci, Jonathan So, Helen Wang, Federica Piccioni, Jessica A. Talamas, David E. Root, William C. Hahn. MYC primes a paralog synthetic lethality involving the mitochondrial transporters TIMM17A and TIMM17B and N-acetylaspartate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB318.