A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer
KRAS mutations play a critical role in driving oncogenic changes across various cancers, particularly in pancreatic ductal adenocarcinoma (PDAC). Approximately 93% of PDAC cases harbor KRAS mutations, with the most common mutations being G12D (around 42% of cases) and G12V (about 32% of cases). The recent approval of sotorasib (AMG510), a selective, covalent KRASG12C inhibitor, for the treatment of non-small cell lung cancer marked a significant milestone in KRAS-targeted therapy. However, there remains an urgent need for the development of additional KRAS inhibitors, particularly for PDAC.
In response, Mirati Therapeutics has developed MRTX1133, a small-molecule, noncovalent, and selective KRASG12D inhibitor, designed through extensive structure-based drug development. Preclinical studies have shown that MRTX1133 exhibits potent antitumor activity both in vitro and in vivo against KRASG12D-mutant cancers, particularly in PDAC, prompting the initiation of a Phase I/II clinical trial. This review summarizes the latest advancements in the use of MRTX1133 for treating KRASG12D-mutant PDAC, highlighting its efficacy and the underlying mechanisms of action. We also explore the challenges and future directions for MRTX1133 therapy in PDAC, including overcoming drug resistance (both intrinsic and acquired), optimizing combination therapies, and enhancing MRTX1133′s oral bioavailability and broader target spectrum. Early preclinical results suggest that MRTX1133 holds significant promise for transforming the treatment of PDAC, potentially reshaping its clinical management.