T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma.

Activating mutations in KRAS drive tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), promoting tumor cell proliferation and contributing to an immunosuppressive tumor microenvironment, rendering PDAC tumors insensitive to immunotherapy. RAS(ON) multi-selective inhibitors, such as daraxonrasib (RMC-6236) and RMC-7977, target the active state of RAS, with potent antitumor activity in PDAC murine models. In this study, we report that RAS(ON) multi-selective inhibition led to rapid and profound PDAC regressions in immunocompetent mice, decreasing myeloid cells and increasing T cells and macrophages in the tumor microenvironment. The depth and duration of tumor regression depended on T cells and conventional dendritic cells. Moreover, the combination of RAS(ON) multi-selective inhibitors with immunotherapy conferred deeper and more durable tumor regressions, including complete responses not seen with either treatment alone. In summary, concurrent inhibition of mutant and wild-type RAS is active in concert with T-cell immunotherapy, revealing RAS(ON) multi-selective inhibitors as a potential therapeutic immuno-sensitizing strategy in PDAC. SIGNIFICANCE: RAS(ON) multi-selective inhibitors enhance antitumor immunity in preclinical models of PDAC, resulting in deeper and more durable responses when combined with immunotherapy. These findings support the clinical evaluation of immune-based strategies that may prolong the response to RAS inhibitor therapies as well as overcome issues of therapeutic resistance to inhibitors alone. See related commentary by Lasse Opsahl and Pasca di Magliano, p. 1537.