Effi cacy of a Small-Molecule Inhibitor of Kras G12D in Immunocompetent Models of Pancreatic Cancer

Mutations in the KRAS oncogene are found in more than 90% of patients with pan-creatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies. SIGNIFICANCE: Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC.

Automated summary

This study evaluated the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in PDAC models with an intact immune system. The results showed that MRTX1133 can induce deep tumor regressions and alter the tumor microenvironment, demonstrating its potential as a novel therapy for PDAC patients. Further clinical testing is warranted.