A Small Molecule with Big Impact: MRTX1133 Targets the KRAS^G12D Mutation in Pancreatic Cancer

KRAS mutations drive oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have KRAS mutations, with G12D (similar to 42% of cases) and G12V (similar to 32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRAS(G12C) inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS-mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, noncovalent, and selective KRAS(G12D) inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent in vitro and in vivo antitumor efficacy against KRAS(G12D)-mutant cancer cells, especially in PDAC, leading to its recent initiation of a phase I/II clinical trial. Here, we provide a summary of the recent advancements related to the use of MRTX1133 for treating KRAS(G12D)-mutant PDAC, focusing on its efficacy and underlying mechanistic actions. In addition, we discuss potential challenges and future directions for MRTX1133 therapy for PDAC, including overcoming intrinsic and acquired drug resistance, developing effective combination therapies, and improving MRTX1133's oral bioavailability and target spectrum. The promising results obtained from preclinical studies suggest that MRTX1133 could revolutionize the treatment of PDAC, bringing about a paradigm shift in its management.