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| Item Type: | Article |
|---|---|
| Title: | Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer |
| Creators: |
Schaufler, D., Ast, D.F.  ORCID: https://orcid.org/0000-0001-6699-0754, Tumbrink, H.L., Abedpour, N., Maas, L., Schwäbe, A.E. ORCID: https://orcid.org/0000-0002-9435-9000, Spille, I., Lennartz, S., Fassunke, J., Aldea, M., Besse, B., Planchard, D., Nogova, L., Michels, S., Kobe, C. ORCID: https://orcid.org/0000-0002-2909-0826, Persigehl, T., Westphal, T., Koleczko, S., Fischer, R., Weber, J.P., Altmüller, J. ORCID: https://orcid.org/0000-0003-4372-1521, Thomas, R.K., Merkelbach-Bruse, S., Gautschi, O., Mezquita, L., Büttner, R. ORCID: https://orcid.org/0000-0001-8806-4786, Wolf, J., Peifer, M. ORCID: https://orcid.org/0000-0002-5243-5503, Brägelmann, J. ORCID: https://orcid.org/0000-0002-1306-2169, Scheffler, M. ORCID: https://orcid.org/0000-0002-9031-1368 and Sos, M.L. ORCID: https://orcid.org/0000-0002-2868-100X
|
| 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 |
| ISSN: | 2397-768X |
| Publisher: | Springer Nature |
| Volume: | 5 |
| Number: | 1 |
| 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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