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 demonstrated robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited 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 proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward 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. [Display omitted] •HRS-4642, a KRAS G12D inhibitor, demonstrated preclinical anti-tumor effects•HRS-4642 treatment led to objective responses in patients with KRAS G12D mutation•Proteasome serves as a sensitization target for HRS-4642 to enhance anti-tumor efficacy•HRS-4642 alone or combined with carfilzomib effectively shaped the tumor microenvironment Zhou et al. report the potent preclinical and clinical anti-tumor efficacy of a KRAS G12D-specific inhibitor, HRS-4642, and its sensitizing combinational strategy with carfilzomib. This work provides novel therapeutics for solid tumor patients harboring KRAS G12D mutation, for whom effective targeted therapies are lacking.