Abstract B082: Clonal dynamics and molecular mechanisms mediating resistance to RAS inhibition

RAS inhibitors (RASi) have the potential to change the clinical landscape for pancreatic ductal adenocarcinoma (PDAC) and improve patient survival. Nevertheless, clinical resistance is likely to reduce the long-term benefits of RASi, and combinations that can bypass or overcome resistance will be needed. Here, we studied the dynamics of resistance to the RAS multi(ON) inhibitor RMC-6236 (daraxonrasib). Prior to frank drug resistance, PDAC cells persist in a drug tolerant state characterized by reduced proliferation; however, only a fraction of the drug-tolerant persister cells contributes to resistance. To identify and study the relevant, resistance-contributing cells, we developed a highly multiplexed, lentiviral DNA barcode system that is compatible with single-cell technologies, enabling paired lineage tracing and phenotypic profiling throughout RASi treatment. Our lineage tracing studies suggest that drug persistence and resistance are fueled by a subset of cells that are primed to survive RASi treatment. Ongoing work is directed at defining and tracking the cell states associated with each stage of resistance emergence. Citation Format: Jayne C. McDevitt, Connor J. Hennessey, Robert Vander Velde, Sydney M. Shaffer, Ben Z. Stanger. Clonal dynamics and molecular mechanisms mediating resistance to RAS inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B082.