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ResearchIn-Press PreviewOncology Open Access | 10.1172/JCI164413

Kras oncogene ablation prevents resistance in advanced lung adenocarcinoma

Marina Salmón,1 Ruth Álvarez-Díaz,1 Coral Fustero-Torre,2 Oksana Brehey,1 Carmen G. Lechuga,3 Manuel Sanclemente,1 Fernando Fernández-García,1 Alejandra López-García,1 María Carmen Martín-Guijarro,4 Sandra Rodríguez-Perales,4 Emily Bousquet-Mur,1 Lucía Morales-Cacho,1 Francisca Mulero,5 Fátima Al-Shahrour,6 Lola Martínez,7 Orlando Domínguez,8 Eduardo Caleiras,9 Sagrario Ortega,10 Carmen Guerra,11 Monica Musteanu,12 Matthias Drosten,13 and Mariano Barbacid14

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Salmón, M. in: JCI | PubMed | Google Scholar |

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Álvarez-Díaz, R. in: JCI | PubMed | Google Scholar |

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Fustero-Torre, C. in: JCI | PubMed | Google Scholar |

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Brehey, O. in: JCI | PubMed | Google Scholar

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Lechuga, C. in: JCI | PubMed | Google Scholar

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Sanclemente, M. in: JCI | PubMed | Google Scholar

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Fernández-García, F. in: JCI | PubMed | Google Scholar |

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by López-García, A. in: JCI | PubMed | Google Scholar

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Martín-Guijarro, M. in: JCI | PubMed | Google Scholar

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Rodríguez-Perales, S. in: JCI | PubMed | Google Scholar |

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Bousquet-Mur, E. in: JCI | PubMed | Google Scholar

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Morales-Cacho, L. in: JCI | PubMed | Google Scholar

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

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1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Al-Shahrour, F. in: JCI | PubMed | Google Scholar |

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Martínez, L. in: JCI | PubMed | Google Scholar

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Domínguez, O. in: JCI | PubMed | Google Scholar |

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

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1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

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1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Guerra, C. in: JCI | PubMed | Google Scholar |

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

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1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Find articles by Drosten, M. in: JCI | PubMed | Google Scholar |

1Molecular Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

3Molecular Oncology, Centro Nacional de Investigaciones Oncologicas Molecular Oncology, Madrid, Spain

4Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

5Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

6Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

7Cytometry Unit, Spanish National Cancer Research Centre (CNIO), madrid, Spain

8Sequencing Department, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

9Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain

10Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

11C/Melchor Fernández Almagro nº3, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

12Experimental Oncology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Madrid, Spain

13Molecular Mechanisms of Cancer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

14Experimmental Oncology, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

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Published March 16, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI164413.
Copyright © 2023, Salmón et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 16, 2023 - Version history
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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 anti-tumor 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.

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