Abstract 5997: Patient-derived cell line and organoid drug screening identifies synergistic PLK1 inhibitor in combination with senolytic ABT-263 for pancreatic cancer

BACKGROUND: Pancreatic cancer (PC) is the 4th deadliest cancer with a 5-year survival rate of only 13%. Chemotherapy remains the standard-of-care to treat PC, but recent retrospective analyses of the Know Your Tumor program found that matched, targeted therapy increases both progression-free survival and overall survival compared to the unmatched chemotherapy group. Therefore, there is a strong need to advance targeted therapy strategies to improve patient outcome in PC. METHODS: To identify new targeted therapies in PC, we utilized a kinase inhibitor library, KCGS 1.0+, that is composed of clinical kinase inhibitors hitting known targets as well as tool compounds against understudied kinases. We screened KCGS 1.0+ against patient-derived xenograft cell line and organoid models representing both the basal-like and classical subtypes of PC. To assess compound sensitivity, we utilized high-content imaging to monitor cell morphology and CellTiterGlo to determine cell viability. RESULTS: We found that overall, organoids were more sensitive than cell lines. 11% of KCGS 1.0+ had an IC50 of 1μM or less for organoids versus only 2% for cell lines. Several known PC targets sensitive to inhibition were recapitulated such as MAPK, PI3K, and CDK7/9 which provided validation for our screening strategy. A top ranked target was PLK1. Organoids were more sensitive to PLK1 inhibition compared to cell lines and cells of the basal-like subtype showed greater sensitivity compared to classical cells. PLK1 overexpression in a subset of basal-like lines was confirmed by western blot. Previous work has shown PLK1 inhibition induces cellular senescence which promotes therapeutic resistance. In our PC lines treated with PLK1 inhibitor and stained with DAPI, we observed enlarged and irregularly shaped nuclei which is a hallmark of senescence. We confirmed senescence by staining for β-galactosidase in PLK1 treated cells. Since senescent cells upregulate the BCL-2 family, we rationalized we could exploit this dependency and combine PLK1 inhibition with the senolytic BCL-2 inhibitor ABT-263. As expected, inhibition of PLK1 and BCL-2 in combination versus either inhibitor alone resulted in dramatic induction of apoptosis measured by Caspase 3/7 activation. CONCLUSIONS: Our high-throughput screen of kinases inhibitors has identified PLK1 as a lethal target in PC. PLK1 inhibition induces cellular senescence, a putative escape mechanism. The combination of PLK1 inhibitor with the senolytic, ABT-263 results in greater cell death compared to either inhibitor alone. This combination strategy advances precision oncology and may have significant implications for patients with the more aggressive basal-like subtype in PC. Citation Format: Madison Jenner, Brian Golitz, Yi Xu, Xianlu Peng, Mohammad Anwar Hossain, David Drewry, Shawn Gomez, Jen Jen Yeh. Patient-derived cell line and organoid drug screening identifies synergistic PLK1 inhibitor in combination with senolytic ABT-263 for pancreatic 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 5997.