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

Abstract

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.