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

Marie-Julie Nokin, Alessia Mira, Enrico Patrucco, Biagio Ricciuti, Sophie Cousin, Isabelle Soubeyran, Sonia San José, Serena Peirone, Livia Caizzi, Sandra Vietti Michelina, Aurelien Bourdon, Xinan Wang, Daniel Alvarez-Villanueva, María Martínez-Iniesta, August Vidal, Telmo Rodrigues, Carmen García-Macías, Mark M. Awad, Ernest Nadal, Alberto Villanueva, Antoine Italiano (), Matteo Cereda (), David Santamaría () and Chiara Ambrogio ()
Additional contact information
Marie-Julie Nokin: IECB
Alessia Mira: Molecular Biotechnology Center, University of Torino
Enrico Patrucco: Molecular Biotechnology Center, University of Torino
Biagio Ricciuti: Dana–Farber Cancer Institute
Sophie Cousin: Institut Bergonié
Isabelle Soubeyran: Institut Bergonié
Sonia San José: IECB
Serena Peirone: Università degli Studi di Milano, Via Celoria 26
Livia Caizzi: Candiolo
Sandra Vietti Michelina: Molecular Biotechnology Center, University of Torino
Aurelien Bourdon: Institut Bergonié
Xinan Wang: Dana–Farber Cancer Institute
Daniel Alvarez-Villanueva: Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat
María Martínez-Iniesta: Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat
August Vidal: Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat
Telmo Rodrigues: Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca
Carmen García-Macías: Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca
Mark M. Awad: Dana–Farber Cancer Institute
Ernest Nadal: Catalan Institute of Oncology (ICO); Preclinical and Experimental Research in Thoracic Tumors (PReTT) Group, Oncobell Program, IDIBELL, L’Hospitalet
Alberto Villanueva: Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat
Antoine Italiano: Institut Bergonié
Matteo Cereda: Università degli Studi di Milano, Via Celoria 26
David Santamaría: IECB
Chiara Ambrogio: Molecular Biotechnology Center, University of Torino

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51828-2

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