Abstract B101: Tumor-selective inhibition of active RAS in pancreatic ductal adenocarcinoma

Abstract

Abstract RM-042 is a broad-spectrum inhibitor of the active (GTP-bound) form of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants (RASMULTI(ON)). Given that more than 90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RM-042 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and remarkable anti-tumor activity across these models following direct RAS inhibition by RM-042 at doses and concentrations that were tolerable in vivo. Analyses of tumor and normal tissues following RM-042 treatment revealed divergent cellular responses to RAS inhibition. While we observed anti-proliferative effects in both normal and tumor tissues, RAS-dependent tumors alone exhibited a susceptibility to cell death via apoptosis within hours of dosing. Finally, using single cell regulatory network analysis, we found that different subtypes of PDAC malignant epithelial cells responded in distinct ways to RAS inhibition by RM-042, resulting in an enrichment of the more differentiated gastro-intestinal lineage state (GLS) cellular subtype. Together, these data have significant implications for the clinical development of RAS inhibitors in the setting of PDAC. A related inhibitor, RMC-6236, is currently in early clinical evaluation (NCT05379985). Citation Format: Urszula N. Wasko, Jingjing Jiang, Lorenzo Tomassoni, Yingyun Wang, Bianca Lee, Margo Orlen, Kristina Drizyte-Miller, Marie Menard, Julien Dilly, Steven A. Sastra, Carmine F. Palermo, Stephanie Chang, Andrew J. Aguirre, Channing J. Der, Robert H. Vonderheide, Ben Z. Stanger, Andrea Califano, Mallika Singh, Kenneth P. Olive. Tumor-selective inhibition of active RAS in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B101.