Identifying immune-mediated mechanisms of RAS inhibitor efficacy and resistance in pancreatic cancer

Oncogenic mutations in KRAS are nearly universal in pancreatic ductal adenocarcinoma (PDAC) and drive disease initiation, progression, and maintenance. Small molecules that inhibit mutant forms of KRAS (KRASi) and both mutant and wildtype RAS proteins (RASi) have recently emerged with the potential to transform the treatment landscape of PDAC. However, the mechanisms dictating efficacy and resistance to RAS inhibitors remain poorly understood. PDAC development and therapeutic response depends on co-evolution and interaction between tumor cells and the tumor immune microenvironment (TIME). This research proposal focuses on a major goal of our laboratories: to determine how remodeling of tumor-immune interactions contributes to efficacy and durability of RAS inhibition. We have developed immunocompetent mouse models that recapitulate seminal features of PDAC heterogeneity and found that while the KRASG12D inhibitor MRTX1133 and the pan-RASGTP inhibitor RMC-6236 both effectively inhibit the MAPK pathway and illicit potent tumor responses in pre-clinical studies, they result in distinct patterns of response and adaptation in tumor cells and the tumor microenvironment. We hypothesize that these differences result from poorly understood and understudied immune cell intrinsic roles of the RAS family that alter interactions between tumor and immune cells in response to RAS inhibition. Using a multidisciplinary and collaborative approach, this proposal integrates cutting-edge genetic models with innovative molecular and immunological methodology to delineate targetable immunological changes which define distinct patterns of response to KRASi and RASi in PDAC. We propose 2 aims that meet the research objectives of notice of special interest NOT-CA-24-016 (Exploratory Cancer Immunology Projects and Technologies (ExCITe)/PA-25-304, by addressing “fundamental aspects of tumor immunology and/or innovative ways to enhance anti-cancer immunity.” Aim 1 will leverage state of the art single cell technology and high dimensional spectral flow cytometry in mouse models of PDAC to comprehensively establish how TIME remodeling contributes to PDAC response and resistance following RASi/KRASi. Aim 2 will investigate immune-intrinsic roles for wild type RAS activity in the PDAC TIME through novel genetic approaches to determine how non tumor cells contribute to efficacy and resistance of RASi. Taken together, this proposal integrates expertise in PDAC pathobiology, tumor immunology, and applies novel genetic tools to unveil new mechanisms that underlie the efficacy and durability of RAS inhibition. Project Number: 1R21CA309360-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: John Milner (+1 co-PI) | Institution: UNIV OF NORTH CAROLINA CHAPEL HILL, CHAPEL HILL, NC | Award Amount: $384,630 | Activity Code: R21 | Study Section: Therapeutic Immune Regulation Study Section[TIR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11287617