Abstract 558: Stearoyl-CoA desaturase is a synthetic lethal target in SMAD4-deficient cancers

Abstract Mothers against decapentaplegic homolog 4, or SMAD4, is a member of the SMAD family of transcription factors that mediate TGF-β signal transduction. SMAD4 loss of function mutation or deletion is found in about 30% of PDAC and 15% of COAD and EAC patients, and it is associated with their poor prognosis. Over the past two decades, its tumor suppressor role has been elucidated, and the loss of SMAD4 is sufficient to promote tumorigenesis in multiple GEM models. To identify novel therapeutic vulnerabilities for SMAD4-deficient cancers, a CRISPR dropout screening approach was employed in SMAD4 isogenic PDAC models. We identified stearoyl-CoA desaturase, SCD, as a synthetic lethal target in SMAD4-deficient context. SCD is critical for de novo lipid biogenesis and catalyzes the rate-limiting step in the production of monounsaturated fatty acid. Genetic and pharmacologic studies in vitro confirmed this synthetic lethal relationship. Additionally, drug-anchored CRISPR dropout screening and RNA expression profiling demonstrated that accumulation of saturated fatty acid in response to SCD inhibition drives cytotoxicity in SMAD4-deficient cells. Mouse studies with CRISPR-based knockout of SCD and a well-characterized SCD inhibitor (A939572) demonstrated anti-tumor efficacy in SMAD4-mutant xenograft models. However, compared to genetic KO of SCD the pharmacological inhibitor was less effective at inhibiting tumor proliferation in vivo. Together, these data identify SCD as a selective vulnerability in SMAD4-mutant cancers. Citation Format: Alvin Lu, Silvia Fenoglio, Hsin-Jung Wu, Minjie Zhang, Alice Tsai, Maria L. Ferdinez, Lauren Grove, Shangtao Liu, Edward Wu, Ashley Choi, Scott Throner, Samuel Meier, Yi Yu, Wenhai Zhang, John Maxwell, Jannik N. Andersen, Teng Teng, Brian B. Haines, Yingnan P. Chen. Stearoyl-CoA desaturase is a synthetic lethal target in SMAD4-deficient cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 558.