KRASG12D inhibition reprograms the tumor microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells

The KRAS G12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRAS G12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRAS G12D , on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRAS G12D -driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8 + effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8 + T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of KRAS G12D in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8 + T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials. Mahadevan et al. demonstrate that the oncogenic KRAS G12D inhibitor MRTX1133 reverses early and advanced PDAC growth and remodels the tumor microenvironment. MRTX1133 induces FAS expression in cancer cells and promotes CD8 + T cell mediated death.