Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer
Authors
- D. Schaufler
- D.F. Ast
- H.L. Tumbrink
- N. Abedpour
- L. Maas
- A.E. Schwäbe
- I. Spille
- S. Lennartz
- J. Fassunke
- M. Aldea
- B. Besse
- D. Planchard
- L. Nogova
- S. Michels
- C. Kobe
- T. Persigehl
- T. Westphal
- S. Koleczko
- R. Fischer
- J.P. Weber
- J. Altmüller
- R.K. Thomas
- S. Merkelbach-Bruse
- O. Gautschi
- L. Mezquita
- R. Büttner
- J. Wolf
- M. Peifer
- J. Brägelmann
- M. Scheffler
- M.L. Sos
Journal
- npj Precision Oncology
Citation
- npj Precis Oncol 5 (1): 102
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.