npj Precision Oncology (Dec 2021)
Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer
- Diana Schaufler,
- David F. Ast,
- Hannah L. Tumbrink,
- Nima Abedpour,
- Lukas Maas,
- Ayla E. Schwäbe,
- Inga Spille,
- Stefanie Lennartz,
- Jana Fassunke,
- Mihaela Aldea,
- Benjamin Besse,
- David Planchard,
- Lucia Nogova,
- Sebastian Michels,
- Carsten Kobe,
- Thorsten Persigehl,
- Theresa Westphal,
- Sophia Koleczko,
- Rieke Fischer,
- Jan-Phillip Weber,
- Janine Altmüller,
- Roman K. Thomas,
- Sabine Merkelbach-Bruse,
- Oliver Gautschi,
- Laura Mezquita,
- Reinhard Büttner,
- Jürgen Wolf,
- Martin Peifer,
- Johannes Brägelmann,
- Matthias Scheffler,
- Martin L. Sos
Affiliations
- Diana Schaufler
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Network Genomic Medicine, Lung Cancer Group Cologne
- David F. Ast
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology
- Hannah L. Tumbrink
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology
- Nima Abedpour
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics
- Lukas Maas
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics
- Ayla E. Schwäbe
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology
- Inga Spille
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology
- Stefanie Lennartz
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology
- Jana Fassunke
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Network Genomic Medicine
- Mihaela Aldea
- Department of medical oncology, Thoracic Group, Gustave Roussy, Villejuif, Paris Sud University Orsay
- Benjamin Besse
- Department of medical oncology, Thoracic Group, Gustave Roussy, Villejuif, Paris Sud University Orsay
- David Planchard
- Department of medical oncology, Thoracic Group, Gustave Roussy, Villejuif, Paris Sud University Orsay
- Lucia Nogova
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Network Genomic Medicine, Lung Cancer Group Cologne
- Sebastian Michels
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Network Genomic Medicine, Lung Cancer Group Cologne
- Carsten Kobe
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Nuclear Medicine
- Thorsten Persigehl
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Diagnostic and Interventional Radiology
- Theresa Westphal
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Network Genomic Medicine, Lung Cancer Group Cologne
- Sophia Koleczko
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Network Genomic Medicine, Lung Cancer Group Cologne
- Rieke Fischer
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Network Genomic Medicine, Lung Cancer Group Cologne
- Jan-Phillip Weber
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Network Genomic Medicine, Lung Cancer Group Cologne
- Janine Altmüller
- Cologne Center for Genomics, University of Cologne
- Roman K. Thomas
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics
- Sabine Merkelbach-Bruse
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Network Genomic Medicine
- Oliver Gautschi
- University of Bern and Cantonal Hospital of Lucerne
- Laura Mezquita
- Medical Oncology Department, Hospital Clinic, Laboratory of Translational Genomics and Targeted therapies in Solid Tumors, IDIBAPS
- Reinhard Büttner
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Network Genomic Medicine
- Jürgen Wolf
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Network Genomic Medicine, Lung Cancer Group Cologne
- Martin Peifer
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics
- Johannes Brägelmann
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology
- Matthias Scheffler
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Network Genomic Medicine, Lung Cancer Group Cologne
- Martin L. Sos
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology
- DOI
- https://doi.org/10.1038/s41698-021-00241-9
- Journal volume & issue
-
Vol. 5,
no. 1
pp. 1 – 12
Abstract
Abstract Activation of MAPK signaling via BRAF mutations may limit the activity of EGFR inhibitors in EGFR-mutant lung cancer patients. However, the impact of BRAF mutations on the selection and fitness of emerging resistant clones during anti-EGFR therapy remains elusive. We tracked the evolution of subclonal mutations by whole-exome sequencing and performed clonal analyses of individual metastases during therapy. Complementary functional analyses of polyclonal EGFR-mutant cell pools showed a dose-dependent enrichment of BRAF V600E and a loss of EGFR inhibitor susceptibility. The clones remain stable and become vulnerable to combined EGFR, RAF, and MEK inhibition. Moreover, only osimertinib/trametinib combination treatment, but not monotherapy with either of these drugs, leads to robust tumor shrinkage in EGFR-driven xenograft models harboring BRAF V600E mutations. These data provide insights into the dynamics of clonal evolution of EGFR-mutant tumors and the therapeutic implications of BRAF co-mutations that may facilitate the development of treatment strategies to improve the prognosis of these patients.
