Abstract 1688: CRISPR-Drug combinatorial screening identifies effective combination treatments for <i>MTAP</i> null cancer

Abstract Homozygous deletion of CDKN2A/MTAP occurs frequently in non-small cell lung cancer and other solid tumors including glioblastoma and pancreatic ductal adenocarcinoma. Lung cancer remains the leading cause of cancer-related mortalities and fewer than 15% of glioblastoma or pancreatic cancer patients survive 5 years underscoring the need for more effective therapies. PRMT5 is a synthetic-lethal dependency in MTAP null tumors and an attractive therapeutic target for CDKN2A/MTAP deleted cancers. A new revolutionary class of inhibitors, referred to as MTA-cooperative PRMT5 inhibitors, has shown promising results in ongoing early phase clinical trials. Nonetheless, effective cancer treatment typically requires therapeutic combinations to improve response rates and defeat emergent resistant clones. Thus, we sought to determine whether perturbation of other pathways could improve the efficacy of MTA-cooperative PRMT5 inhibitors. Using a paralog and single gene targeting CRISPR library we screened MTAP deleted cancers in the presence or absence of PRMT5 inhibitors. We identified several genes sensitizing to PRMT5 inhibition including members of the MAP kinase pathway. We demonstrate that genetic depletion or chemical inhibition of MAP kinase pathway members using KRAS, MEK, ERK, and RAF inhibitors synergize with PRMT5 inhibition to kill CDKN2A/MTAP null, RAS-active tumors. Further, MTA-cooperative PRMT5 inhibitors combined with either KRAS or RAF inhibitors led to durable in vivo complete responses, emphasizing the potential benefit for patients. Citation Format: Nikola Knoll, Sarah Masser, Devishi Kesar, Eliana Destefanis, Guangyan Li, Blanka Bordas, Jayu Jen, Yao He, Srivatsan Raghavan, William Sellers, Kathleen M. Mulvaney. CRISPR-Drug combinatorial screening identifies effective combination treatments for MTAP null cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1688.