Abstract LB232: Targeting MEK activity in pancreatic tumors resistant to the combination of 5FU, irinotecan, and oxaliplatin promotes response to immunotherapy

Abstract

Abstract FOLFIRINOX, a chemotherapy regimen consisting of 5FU, Leucovorin, Irinotecan, and Oxaliplatin, has been a first-line standard of care for patients with pancreatic adenocarcinoma (PDAC) for the last decade. However, low patient survival rates following treatment highlight frequent occurrence of resistance. Hence there is increasing interest in developing appropriate models of FOLFIRINOX resistance to identify subsequent line therapies. We have generated PDAC cell lines that exhibit acquired resistance to a combination of 5FU (F), Irinotecan (I), and Oxaliplatin (O) (FIO) in vitro. In mice, they form tumors that resemble FOLFIRINOX neoadjuvant-treated PDAC patients in regard to immune cell infiltration and a lack of response to single-agent anti-PD-1 therapy. We also show that similar to human PDAC tumors treated with neoadjuvant FOLFIRINOX, FIO-resistant tumors exhibit increased ERK1/2 phosphorylation. We demonstrate that the MEK inhibitor Trametinib reprograms the FIO-resistant tumors, but not the parental tumors, towards a less immunosuppressive tumor immune microenvironment. Importantly, Trametinib sensitizes FIO-resistant tumors to anti-PD-1 therapy, with the combination treatment significantly enhancing the cytolytic activity of the infiltrating CD8 + T cells and increasing tumor cell death. Taken together, our findings identify enhanced MEK/ERK signaling as a therapeutic target in FOLFIRINOX-resistant PDAC tumors, and suggest evaluating the combination of Trametinib and anti-PD-1 therapy in patients who progress on FOLFIRINOX. Citation Format: Thao D. Pham, Anastasia E. Metropulos, Nida Mubin, Dhavan N. Shah, Christina Spaulding, Mario Shields, David J. Bentrem, Hidayatullah G. Munshi. Targeting MEK activity in pancreatic tumors resistant to the combination of 5FU, irinotecan, and oxaliplatin promotes response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB232.