Abstract 494: Identifying vulnerabilities in basal-like pancreatic adenocarcinoma (PDAC)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, with a 5-year survival of only 12.5%. There are two transcriptomic PDAC tumor subtypes: classical and basal-like. Basal-like PDAC is associated with worse patient outcomes and does not respond to the standard-of-care chemotherapeutic regimen FOLFIRINOX; new therapeutic strategies effective in basal-like PDAC are needed. To identify essential targets in basal-like PDAC, we designed a CRISPR library targeting 394 highly expressed basal-like exemplar genes and performed the screen basal-like cell lines derived from PDAC patient-derived xenograft (PDX) tumors. We found 46% of the library genes were essential (181/394, p<0.05), with the top Reactome pathways represented by essential genes being polo-like kinase mediated events, cell cycle checkpoints, formation of the cornified envelope, and Type I hemidesmosome assembly. Of 8 top lethal genes, 7 were validated. One of these validated targets was integrin subunit alpha 3 (ITGA3). Integrins are cell surface receptors that interact with extracellular matrix proteins, the cytoskeleton, as well as downstream effectors important in cancer signaling. ITGA3 was required for colony formation in basal-like PDX-derived cell lines. In basal-like organoids, shRNA knockdown of ITGA3 reduced growth compared to classical organoids. We report promising targets for basal-like PDAC that may play a role in subtype-specific biology and therapeutic response. Citation Format: Sandra Zarmer, Ian McCabe, Jen Jen Yeh. Identifying vulnerabilities in basal-like pancreatic adenocarcinoma (PDAC) [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 494.