Abstract 1948: Resistance to RAS inhibition promotes remodeling of the immunosuppressive microenvironment of pancreatic cancer

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely due to acquired chemotherapy resistance. MRTX-1133, a promising KRAS-G12D inhibitor, has demonstrated initial efficacy; however, resistance analogous to that seen with KRAS-G12C inhibitors is an emerging challenge. The tumor microenvironment (TME) is increasingly recognized as a contributor to resistance, often fostering tumor survival and immune evasion. Methods: To elucidate the resistance mechanisms to KRAS-G12D inhibition, we established resistant mouse and human PDAC cell lines derived from mouse and human models. These models were analyzed using flow cytometry and single cell RNA sequencing to define TME dynamics as resistant is acquired and after is has been established. We also analyzed cytokines released by resistant tumor cells using protein arrays and RNA sequencing. Results: Our investigation revealed significant TME alterations associated with acquired resistance. Notably, there was a marked increase in the population CD4+ Tregs and neutrophil while activated CD8+ T cells are decreased in the resistant tumors. Concurrently, an increased secretion of chemokines such as CXCL1 and CXCL2 was observed in resistant tumor cells relative to their parental counterparts. Conclusions: The adaptation of PDAC to circumvent KRAS inhibition involves a distinct reprogramming of the TME, attenuating immune surveillance and potentially facilitating tumor progression. Current efforts are directed towards delineating the key pathways implicated in these TME modifications to pioneer new therapeutic approaches for managing KRAS inhibitor resistant PDAC. Citation Format: Herve Tiriac. Resistance to RAS inhibition promotes remodeling of the immunosuppressive microenvironment of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1948.