Abstract 5819: Tumor nutrient conditions confer drug resistance in pancreatic cancer

Abstract

Abstract Drug resistance is a major obstacle to the treatment of pancreatic ductal adenocarcinoma (PDAC). Current standard of care includes combination chemotherapies; however, the majority of patients fail to respond to these treatments. Despite significant advances in our understanding of PDAC biology, it remains unclear what biological processes drives the drug resistance observed in most PDAC cases. Contributing to our limited understanding of this problem, in vitro models of PDAC fail to recapitulate in vivo drug resistance, suggesting the tumor microenvironment is a critical regulator.A defining feature of PDAC tumors is an abnormal nutrient environment, which may carry important biological cues driving many of the undesirable cell behaviors related to disease progression. Using a novel medium formulation that mimics the nutrient conditions observed within PDAC tumors (TIFM), we find that PDAC cells cultured in TIFM become highly resistant to common chemotherapeutic agents, better recapitulating the in vivo drug resistance phenotype than standard cultures. Several of these agents engage with their intended target in TIFM cultured cells, discouraging the idea that drug resistance is primarily mediated by drug efflux. However, TIFM cultured cells display reduced apoptotic priming, enabling their survival to drug exposure. Drug resistance enabled by TIFM nutrients is not immediately reversible with standard culture and can be inherited over multiple cell generations. Consistent with this, we find that TIFM nutrient conditions results in significant alterations to the epigenetic landscape of pancreatic cancer cells, rewiring expression of genes that may function as critical regulators of cell survival in PDAC. Ultimately, the work from this project will help elucidate how poor nutrient perfusion within solid tumors regulates cell survival processes and may lead towards better treatment options for PDAC patients beyond combination chemotherapy. Citation Format: Colin Sheehan, James Martin, Grace Croley, Joshua McKeever, Anika Thomas-Toth, Patrick Jonker, James LaBelle, Andrew Koh, Alexander Muir. Tumor nutrient conditions confer drug resistance in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5819.