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

• Published in: Nature communications Vol. 15; no. 1; pp. 7554 - 18
• Main Authors: 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
• Format: Journal Article Web Resource
• Language: English
• Published: London Nature Publishing Group UK 30-08-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/31; 13/44; 13/95; 631/67/1059/2326; 631/67/1612/1350; 64/60; Acetonitriles; Animals; Biopsy; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell culture; Cell Line, Tumor; Covalence; Drug delivery; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Guanosine triphosphate; Guanosine Triphosphate - metabolism; Health services; Human health sciences; Humanities and Social Sciences; Humans; Inhibitors; K-Ras protein; Load resistance; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; multidisciplinary; Mutation; Non-small cell lung carcinoma; Oncogenes; Oncologie; Oncology; Patients; Piperazines; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Pyridines; Pyrimidines; Science; Science (multidisciplinary); Sciences de la santé humaine; Sequences; Small cell lung carcinoma; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51828-2

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 targets the active GTP-bound (ON) state of the oncogene, we provide a proof-of-concept that the clinical stage KRAS
G12C
(ON) inhibitor RMC-6291 alone or in combination with KRAS
G12C
(OFF) drugs can be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS-GTP loading.
KRAS G12C mutant selective inhibitors targeting inactive state have been approved for use in non-small cell lung cancer (NSCLC). Here, using models derived from a patient with NSCLC who progressed on sotorasib (KRAS G12C inhibitor), the authors identify increased KRAS GTP loading as an adaptive resistance mechanism which could be targeted with KRAS G12C inhibitors selective to the GTP active state.