2. Academic Validation
  3. Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas

Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas

  • J Clin Invest. 2023 Apr 3;133(7):e164413. doi: 10.1172/JCI164413.
Marina Salmón 1,  Ruth Álvarez-Díaz 1,  Coral Fustero-Torre 2,  Oksana Brehey 1,  Carmen G Lechuga 1,  Manuel Sanclemente 1,  Fernando Fernández-García 1,  Alejandra López-García 1,  María Carmen Martín-Guijarro 3,  Sandra Rodríguez-Perales 3,  Emily Bousquet-Mur 1,  Lucía Morales-Cacho 1,  Francisca Mulero 4,  Fátima Al-Shahrour 2,  Lola Martínez 5,  Orlando Domínguez 6,  Eduardo Caleiras 7,  Sagrario Ortega 8,  Carmen Guerra 1 9,  Monica Musteanu 1 9 10,  Matthias Drosten 1 9 11,  Mariano Barbacid 1 9
Affiliations

Affiliations

  • 1 Experimental Oncology Group, Molecular Oncology Program.
  • 2 Bioinformatics Unit.
  • 3 Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program.
  • 4 Molecular Imaging Unit.
  • 5 Flow Cytometry Unit.
  • 6 Genomics Unit.
  • 7 Histopathology Unit, and.
  • 8 Mouse Genome Editing Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
  • 9 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.
  • 10 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University, Madrid, Spain.
  • 11 Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC) and Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Consejo Superior de Investigaciones Científicas-Universidad de Salamanca (CSIC-USAL), Salamanca, Spain.
PMID: 36928090 DOI: 10.1172/JCI164413
Abstract

KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.

Keywords

Drug therapy; Lung cancer; Oncogenes; Oncology.

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