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

Author

Listed:
  • Marie-Julie Nokin

    (IECB
    GIGA-Cancer, University of Liège)

  • 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
    Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca)

  • Serena Peirone

    (Università degli Studi di Milano, Via Celoria 26
    Candiolo)

  • 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
    Catalan Institute of Oncology (ICO); Preclinical and Experimental Research in Thoracic Tumors (PReTT) Group, Oncobell Program, IDIBELL, L’Hospitalet)

  • Antoine Italiano

    (Institut Bergonié)

  • Matteo Cereda

    (Università degli Studi di Milano, Via Celoria 26
    Candiolo)

  • David Santamaría

    (IECB
    Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca)

  • Chiara Ambrogio

    (Molecular Biotechnology Center, University of Torino)

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.

Suggested Citation

  • 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 , 2024. "RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51828-2
    DOI: 10.1038/s41467-024-51828-2
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    References listed on IDEAS

    as
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