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

Autor: Nokin MJ; INSERM U1312, University of Bordeaux, IECB, Pessac, France.; Laboratory of Biology of Tumor and Development (LBTD), GIGA-Cancer, University of Liège, Liège, Belgium., Mira A; Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy., Patrucco E; Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy., Ricciuti B; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Cousin S; Department of Medical Oncology, Institut Bergonié, Bordeaux, France., Soubeyran I; Department of Biopathology, Institut Bergonié, Bordeaux, France., San José S; INSERM U1312, University of Bordeaux, IECB, Pessac, France.; Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain., Peirone S; Department of Biosciences, Università degli Studi di Milano, Via Celoria 26, Milan, Italy.; Italian Institute for Genomic Medicine, c/o IRCCS, Str. Prov. le 142, km 3.95, Candiolo, Torino, Italy., Caizzi L; Italian Institute for Genomic Medicine, c/o IRCCS, Str. Prov. le 142, km 3.95, Candiolo, Torino, Italy., Vietti Michelina S; Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy., Bourdon A; Department of Biopathology, Institut Bergonié, Bordeaux, France., Wang X; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Alvarez-Villanueva D; Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain., Martínez-Iniesta M; Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain., Vidal A; Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain., Rodrigues T; Comparative Pathology Unit, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain., García-Macías C; Comparative Pathology Unit, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain., Awad MM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Nadal E; Department of Medical Oncology, Catalan Institute of Oncology (ICO); Preclinical and Experimental Research in Thoracic Tumors (PReTT) Group, Oncobell Program, IDIBELL, L'Hospitalet, Barcelona, Spain., Villanueva A; Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.; Department of Medical Oncology, Catalan Institute of Oncology (ICO); Preclinical and Experimental Research in Thoracic Tumors (PReTT) Group, Oncobell Program, IDIBELL, L'Hospitalet, Barcelona, Spain., Italiano A; Department of Medical Oncology, Institut Bergonié, Bordeaux, France. a.italiano@bordeaux.unicancer.fr., Cereda M; Department of Biosciences, Università degli Studi di Milano, Via Celoria 26, Milan, Italy. matteo.cereda@iigm.it.; Italian Institute for Genomic Medicine, c/o IRCCS, Str. Prov. le 142, km 3.95, Candiolo, Torino, Italy. matteo.cereda@iigm.it., Santamaría D; INSERM U1312, University of Bordeaux, IECB, Pessac, France. d.santamaria@usal.es.; Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain. d.santamaria@usal.es., Ambrogio C; Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy. chiara.ambrogio@unito.it.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 30; Vol. 15 (1), pp. 7554. Date of Electronic Publication: 2024 Aug 30.
DOI: 10.1038/s41467-024-51828-2
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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