Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer.

Autor:	Schaufler D; 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, Cologne, Germany., Ast DF; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; Mildred Scheel School of Oncology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Tumbrink HL; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany., Abedpour N; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany., Maas L; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany., Schwäbe AE; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany., Spille I; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany., Lennartz S; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany., Fassunke J; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Network Genomic Medicine, Cologne, Germany., Aldea M; Department of medical oncology, Thoracic Group, Gustave Roussy, Villejuif, Paris Sud University Orsay, Paris, France., Besse B; Department of medical oncology, Thoracic Group, Gustave Roussy, Villejuif, Paris Sud University Orsay, Paris, France., Planchard D; Department of medical oncology, Thoracic Group, Gustave Roussy, Villejuif, Paris Sud University Orsay, Paris, France., Nogova L; 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, Cologne, Germany., Michels S; 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, Cologne, Germany., Kobe C; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Nuclear Medicine, Cologne, Germany., Persigehl T; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Diagnostic and Interventional Radiology, Cologne, Germany., Westphal T; 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, Cologne, Germany., Koleczko S; 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, Cologne, Germany., Fischer R; 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, Cologne, Germany., Weber JP; 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, Cologne, Germany., Altmüller J; Cologne Center for Genomics, University of Cologne, Cologne, Germany., Thomas RK; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Network Genomic Medicine, Cologne, Germany.; DKFZ, German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg, Germany., Merkelbach-Bruse S; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Network Genomic Medicine, Cologne, Germany., Gautschi O; University of Bern and Cantonal Hospital of Lucerne, Lucerne, Switzerland., Mezquita L; Medical Oncology Department, Hospital Clinic, Laboratory of Translational Genomics and Targeted therapies in Solid Tumors, IDIBAPS, Barcelona, Spain., Büttner R; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Network Genomic Medicine, Cologne, Germany., Wolf J; 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, Cologne, Germany., Peifer M; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany., Brägelmann J; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology, Cologne, Germany. johannes.braegelmann@uni-koeln.de.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany. johannes.braegelmann@uni-koeln.de.; Mildred Scheel School of Oncology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. johannes.braegelmann@uni-koeln.de.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany. johannes.braegelmann@uni-koeln.de., Scheffler M; 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, Cologne, Germany. matthias.scheffler@uk-koeln.de., Sos ML; University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Molecular Pathology, Cologne, Germany. martin.sos@uni-koeln.de.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany. martin.sos@uni-koeln.de.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany. martin.sos@uni-koeln.de.
Jazyk:	angličtina
Zdroj:	NPJ precision oncology [NPJ Precis Oncol] 2021 Dec 17; Vol. 5 (1), pp. 102. Date of Electronic Publication: 2021 Dec 17.
DOI:	10.1038/s41698-021-00241-9
Abstrakt:	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. (© 2021. The Author(s).)
Databáze:	MEDLINE
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