Novel RAS ON inhibitors overcome clinical resistance to KRAS G12C covalent blockade

Selective KRAS-G12C inhibitors have been developed that covalently lock the oncogene in the inactive GDP bound state. Two of these molecules, sotorasib and adagrasib, have been FDA approved for the treatment of adult patients with KRAS G12C mutated previously treated advanced NSCLC. 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 tumours. We demonstrate here that disease progression in vivo can also occur due to adaptive mechanisms and increased KRAS GTP loading concomitantly with genetic abnormalities. Using the preclinical tool tricomplex KRAS G12C selective covalent inhibitor, RMC4998, that targets the active GTP bound ON state of the oncogene, we provide a proof of concept that a clinical stage KRAS G12C ON inhibitor RMC6291 could be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS GTP loading.