Abstract PR023: Targeting gemcitabine resistance in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a devastating 5-year survival rate of 11%. A lack of durable responses to standard-of-care chemotherapy combinations renders its treatment particularly challenging and largely contributes to the devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDAC therapy, but resistance remains a major hurdle. Multiple mechanisms of chemoresistance have been suggested to be mediated by rewired metabolism in PDAC cells. Accordingly, we hypothesize that metabolic reprogramming can be targeted to re-sensitize PDAC tumors to anti-metabolite chemotherapy. To define the spectrum of targetable metabolic and transcriptomic programs that drive cell-intrinsic resistance to gemcitabine, we established organoids from treatment-naïve PDAC patients. Gemcitabine high versus low responders, as assessed by dose response viability assays, were selected for metabolomic profiling and RNA sequencing. To define real-time reprogramming during the acquisition of resistance, we generated gemcitabine resistant murine pancreatic cancer cell lines and collected a time course series of metabolomic and transcriptomic datasets of sensitive, intermediate resistant and resistant cells. Integration of these dataset through a systems biology approach to define primary and de novo resistance is being used to characterize metabolic gemcitabine resistance mechanisms. These are functionally validated to provide novel approaches to re-sensitize resistant PDAC cells to gemcitabine in vitro and in vivo. The improvement of current chemotherapy combinations represents a promising approach, with potential to immediately translate into a clinical benefit and improve survival in this deadly disease. Citation Format: Alica Katrin Beutel, Rima Singh, Cecily Anaraki, Gregory Tong, Thomas Martinez, Alexander Kleger, Zeljka Jutric, Christopher James Halbrook. Targeting gemcitabine resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR023.