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

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Item Type:Article
Title:Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer
Creators Name:Schaufler, D. and Ast, D.F. and Tumbrink, H.L. and Abedpour, N. and Maas, L. and Schwäbe, A.E. and Spille, I. and Lennartz, S. and Fassunke, J. and Aldea, M. and Besse, B. and Planchard, D. and Nogova, L. and Michels, S. and Kobe, C. and Persigehl, T. and Westphal, T. and Koleczko, S. and Fischer, R. and Weber, J.P. and Altmüller, J. and Thomas, R.K. and Merkelbach-Bruse, S. and Gautschi, O. and Mezquita, L. and Büttner, R. and Wolf, J. and Peifer, M. and Brägelmann, J. and Scheffler, M. and Sos, M.L.
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 mutations. These data provide insights into the dynamics of clonal evolution of EGFR-mutant tumors and the therapeutic implications of BRAF(V600E) co-mutations that may facilitate the development of treatment strategies to improve the prognosis of these patients.
Keywords:Animals, Mice
Source:npj Precision Oncology
Publisher:Springer Nature
Page Range:102
Date:17 December 2021
Official Publication:https://doi.org/10.1038/s41698-021-00241-9
PubMed:View item in PubMed

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