npj Precision Oncology (Dec 2021)

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

  • 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

Journal volume & issue
Vol. 5, no. 1
pp. 1 – 12


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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.