RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade
Selective KRAS<sup>G12C</sup> 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<sup>G12C</sup>-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<sup>G12C</sup>-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<sup>G12C</sup>(ON) inhibitor RMC-6291 alone or in combination with KRAS<sup>G12C</sup>(OFF) drugs can be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS-GTP loading.
Authors
- Daniel Alvarez-Villanueva
- August Vidal (ORCID: https://orcid.org/0000-0001-5727-2099)
- Alberto Villanueva (ORCID: https://orcid.org/0000-0001-5164-0006)
- Xinan Wang (ORCID: https://orcid.org/0000-0001-5236-1105)
- Sonia San José
- Ernest Nadal (ORCID: https://orcid.org/0000-0002-9674-5554)
- Chiara Ambrogio (ORCID: https://orcid.org/0000-0003-4122-701X)
- Telmo Rodrigues (ORCID: https://orcid.org/0000-0002-3826-0997)
- Biagio Ricciuti (ORCID: https://orcid.org/0000-0002-0651-2678)
- Livia Caizzi (ORCID: https://orcid.org/0000-0001-9723-6893)
- Marie‐Julie Nokin
- María Carmen García-Macías (ORCID: https://orcid.org/0000-0002-5929-4926)
- David Santamarı́a (ORCID: https://orcid.org/0000-0002-4711-3569)
- Antoîne Italiano (ORCID: https://orcid.org/0000-0002-8540-5351)
- Aurélien Bourdon (ORCID: https://orcid.org/0009-0007-9907-6214)
- Matteo Cereda (ORCID: https://orcid.org/0000-0003-1799-5537)
- Serena Peirone (ORCID: https://orcid.org/0000-0002-5195-7908)
- Sandra Vietti Michelina (ORCID: https://orcid.org/0009-0007-3777-4906)
- Mark M. Awad (ORCID: https://orcid.org/0000-0003-0928-5244)
- Alessia Mira (ORCID: https://orcid.org/0000-0002-8456-8159)
- María Martínez‐Iniesta (ORCID: https://orcid.org/0000-0001-6252-6671)
- Enrico Patrucco (ORCID: https://orcid.org/0000-0001-8060-5058)
- Sophie Cousin (ORCID: https://orcid.org/0000-0002-4847-6329)
- Isabelle Soubeyran
Institutions
- Institut Català d'Ornitologia (ES)
- Université de Bordeaux (FR)
- Inserm (FR)
- University of Liège (BE)
- Universidad de Salamanca (ES)
- University of Milan (IT)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Institut Català d'Oncologia (ES)
- Dana-Farber Cancer Institute (US)
- Italian institute for Genomic Medicine (IT)
- Institut Bergonié (FR)
- Centro de Investigación del Cáncer (ES)
- Institut Européen de Chimie et Biologie (FR)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- BoRdeaux Institute of onCology (FR)
- University of Turin (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1038/s41467-024-51828-2
- Citations
- 48
- Primary Topic
- Adenosine and Purinergic Signaling
- Type
- article
- Field-Weighted Citation Impact
- 19.32
Funders
- Giovanni Armenise-Harvard Foundation
- Compagnia di San Paolo
- Revolution Medicines
- European Commission
- Institut National de la Santé et de la Recherche Médicale
- Generalitat de Catalunya
- Fédération Wallonie-Bruxelles
- Ministerio de Economía y Competitividad
- Ministerio de Ciencia e Innovación
- Associazione Italiana per la Ricerca sul Cancro
- Université de Bordeaux
- Institut National Du Cancer
- Instituto de Salud Carlos III
- European Regional Development Fund