| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
npj Precision Oncology, Vol 5, Iss 1, Pp 1-12 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2397-768X |
| DOI: |
10.1038/s41698-021-00241-9 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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