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


  • 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


  • npj Precision Oncology


  • npj Precis Oncol 5 (1): 102


  • 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.