Data di Pubblicazione:
2024
Abstract:
: Selective KRASG12C 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 KRASG12C-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 KRASG12C-selective covalent inhibitor, RMC-4998 (also known as RM-029), that targets the active GTP-bound (ON) state of the oncogene, we provide a proof-of-concept that the clinical stage KRASG12C(ON) inhibitor RMC-6291 alone or in combination with KRASG12C(OFF) drugs can be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS-GTP loading.
Tipologia CRIS:
03A-Articolo su Rivista
Elenco autori:
Nokin, Marie-Julie; Mira, Alessia; Patrucco, Enrico; Ricciuti, Biagio; Cousin, Sophie; Soubeyran, Isabelle; San José, Sonia; Peirone, Serena; Caizzi, Livia; Vietti Michelina, Sandra; Bourdon, Aurelien; Wang, Xinan; Alvarez-Villanueva, Daniel; Martínez-Iniesta, María; Vidal, August; Rodrigues, Telmo; García-Macías, Carmen; Awad, Mark M.; Nadal, Ernest; Villanueva, Alberto; Italiano, Antoine; Cereda, Matteo; Santamaría, David; Ambrogio, Chiara
Link alla scheda completa:
Pubblicato in: