Abstract B089: Identification of novel drivers of gemcitabine resistance in pancreatic cancer

Abstract Pancreatic cancer is an aggressive disease with limited therapeutic options. Gemcitabine is a clinically used chemotherapy for pancreatic cancer treatment but has limited efficacy. The molecular mechanisms responsible for gemcitabine resistance in pancreatic cancer are still unclear. Here, we analyzed the genomics of drug sensitivity in cancer dataset and identified various pancreatic cancer cells with distinct sensitivity to gemcitabine. Validation with proliferation and clonogenic assays confirmed that while CFPAC1 and PANC0327 are highly gemcitabine-sensitive, ASPC1 and PANC1 display intrinsic gemcitabine resistance. Analysis of the gene expression profile of these cells identified several genes that are differentially upregulated in resistant versus sensitive cells. Pathway enrichment analysis using the differential genes revealed the upregulation of Hippo, Wnt, MAPK signaling pathways as well as autophagy and glutathione metabolism in the resistant cells. Using quantitative PCR, immunoblotting and biochemical assays, and extracellular flux analysis methods, we have characterized the molecular distinctions between gemcitabine sensitive and resistant cells. Our results provide insight on the molecular mechanisms driving gemcitabine resistance in pancreatic cancer and could lead to novel therapeutic strategies to overcome resistance and improve patients’ treatment. Citation Format: Amina D Bilalbegovic, Bowen Fu, Zeribe Nwosu. Identification of novel drivers of gemcitabine resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B089.