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Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer
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 subclon...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683498/ https://www.ncbi.nlm.nih.gov/pubmed/34921211 http://dx.doi.org/10.1038/s41698-021-00241-9 |
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author | Schaufler, Diana Ast, David F. Tumbrink, Hannah L. Abedpour, Nima Maas, Lukas Schwäbe, Ayla E. Spille, Inga Lennartz, Stefanie Fassunke, Jana Aldea, Mihaela Besse, Benjamin Planchard, David Nogova, Lucia Michels, Sebastian Kobe, Carsten Persigehl, Thorsten Westphal, Theresa Koleczko, Sophia Fischer, Rieke Weber, Jan-Phillip Altmüller, Janine Thomas, Roman K. Merkelbach-Bruse, Sabine Gautschi, Oliver Mezquita, Laura Büttner, Reinhard Wolf, Jürgen Peifer, Martin Brägelmann, Johannes Scheffler, Matthias Sos, Martin L. |
author_facet | Schaufler, Diana Ast, David F. Tumbrink, Hannah L. Abedpour, Nima Maas, Lukas Schwäbe, Ayla E. Spille, Inga Lennartz, Stefanie Fassunke, Jana Aldea, Mihaela Besse, Benjamin Planchard, David Nogova, Lucia Michels, Sebastian Kobe, Carsten Persigehl, Thorsten Westphal, Theresa Koleczko, Sophia Fischer, Rieke Weber, Jan-Phillip Altmüller, Janine Thomas, Roman K. Merkelbach-Bruse, Sabine Gautschi, Oliver Mezquita, Laura Büttner, Reinhard Wolf, Jürgen Peifer, Martin Brägelmann, Johannes Scheffler, Matthias Sos, Martin L. |
author_sort | Schaufler, Diana |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8683498 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86834982022-01-04 Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer Schaufler, Diana Ast, David F. Tumbrink, Hannah L. Abedpour, Nima Maas, Lukas Schwäbe, Ayla E. Spille, Inga Lennartz, Stefanie Fassunke, Jana Aldea, Mihaela Besse, Benjamin Planchard, David Nogova, Lucia Michels, Sebastian Kobe, Carsten Persigehl, Thorsten Westphal, Theresa Koleczko, Sophia Fischer, Rieke Weber, Jan-Phillip Altmüller, Janine Thomas, Roman K. Merkelbach-Bruse, Sabine Gautschi, Oliver Mezquita, Laura Büttner, Reinhard Wolf, Jürgen Peifer, Martin Brägelmann, Johannes Scheffler, Matthias Sos, Martin L. NPJ Precis Oncol Article 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. Nature Publishing Group UK 2021-12-17 /pmc/articles/PMC8683498/ /pubmed/34921211 http://dx.doi.org/10.1038/s41698-021-00241-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Schaufler, Diana Ast, David F. Tumbrink, Hannah L. Abedpour, Nima Maas, Lukas Schwäbe, Ayla E. Spille, Inga Lennartz, Stefanie Fassunke, Jana Aldea, Mihaela Besse, Benjamin Planchard, David Nogova, Lucia Michels, Sebastian Kobe, Carsten Persigehl, Thorsten Westphal, Theresa Koleczko, Sophia Fischer, Rieke Weber, Jan-Phillip Altmüller, Janine Thomas, Roman K. Merkelbach-Bruse, Sabine Gautschi, Oliver Mezquita, Laura Büttner, Reinhard Wolf, Jürgen Peifer, Martin Brägelmann, Johannes Scheffler, Matthias Sos, Martin L. Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer |
title | Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer |
title_full | Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer |
title_fullStr | Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer |
title_full_unstemmed | Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer |
title_short | Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer |
title_sort | clonal dynamics of braf-driven drug resistance in egfr-mutant lung cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683498/ https://www.ncbi.nlm.nih.gov/pubmed/34921211 http://dx.doi.org/10.1038/s41698-021-00241-9 |
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