Anti-tumor Efficacy of HRS-4642 and Its Potential Combination with Proteasome Inhibition in KRAS G12D-mutant Cancer

KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrats robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibits promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR/Cas9 screening, which unveiled the proteasome as a synergistic target. We further observed that the proteasome inhibitor, carfilzomib, prominently improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, especially when combined with carfilzomib, significantly reshapes the tumor microenvironment towards an immune permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.