Abstract 4023: Low nutrient availability drives increased macropinocytosis and MEK inhibitor resistance in KRASG12R-mutant pancreatic ductal adenocarcinoma

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third most deadly human cancer with a dismal five-year survival rate of 10%. KRAS is mutated in over 95% of PDAC tumors and is a key driver of PDAC tumorigenesis. Mutant KRAS is constitutively active and drives proliferation through the upregulation of numerous signaling and metabolic pathways to support tumor proliferation. Despite the promise of targeted inhibitors of the RAF-MEK-ERK MAPK signaling pathway, arguably the most critical RAS-mediated proliferative signaling pathway, clinical trials targeting oncogenic MEK/ERK signaling as a single-agent therapy have been unsuccessful. The PDAC tumor microenvironment has been shown to be depleted of glutamine and free amino acids, suggesting that PDAC relies heavily on nontraditional metabolic processes for proliferation such as macropinocytosis, the nonselective uptake of proteins and molecules from extracellular spaces, and autophagy, a mode of cellular recycling. Macropinocytosis has been shown to be elevated in PDAC cell lines and human tumors. Despite recent findings describing the limited nutrient availability in the tumor microenvironment, cell culture studies supporting the use of MEK/ERK inhibitors are predominately performed in a high glutamine medium. By utilizing a minimal glutamine medium supplemented with bovine serum albumin, a large protein that is absorbed via macropinocytosis, we show that this growth medium drives resistance to MEK MAPK inhibition. To evaluate whether PDAC cells proliferating in a low glutamine medium can be sensitized to MEK inhibition, we have performed a CRISPR/Cas9 loss-of-function screen targeting the druggable genome to determine effective therapeutic combinations under these conditions. To follow up on our in vitro screen, we will evaluate the therapeutic efficacy of our findings with 2D and 3D PDAC proliferation assays. These studies will describe novel treatment strategies for PDAC patients with elevated macropinocytosis. Citation Format: Amanda Linke, Rachel Burge, Aaron Hobbs. Low nutrient availability drives increased macropinocytosis and MEK inhibitor resistance in KRASG12R-mutant pancreatic ductal adenocarcinoma [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 4023.