Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer.
Cancer Cell
; 42(7): 1286-1300.e8, 2024 Jul 08.
Article
in En
| MEDLINE
| ID: mdl-38942026
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Proto-Oncogene Proteins p21(ras)
/
Proteasome Inhibitors
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Mutation
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Cancer Cell
Journal subject:
NEOPLASIAS
Year:
2024
Document type:
Article