RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade.

ABSTRACT: Selective KRAS^G12C inhibitors have been developed to covalently lock the oncogene in the inactive GDP-bound state. Two of these molecules, sotorasib and adagrasib, are approved for the treatment of adult patients with KRAS^G12C-mutated previously treated advanced non-small cell lung cancer. Drug treatment imposes selective pressures leading to the outgrowth of drug-resistant variants. Mass sequencing from patients' biopsies identified a number of acquired KRAS mutations -both in cis and in trans- in resistant tumors. We demonstrate here that disease progression in vivo can also occur due to adaptive mechanisms and increased KRAS-GTP loading. Using the preclinical tool tri-complex KRAS^G12C-selective covalent inhibitor, RMC-4998 (also known as RM-029), that ta

SUBMITTER: Nokin MJ 

PROVIDER: S-EPMC11364849 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature