BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy

Douglas B. Johnson*, Merrida A. Childress, Zachary R. Chalmers, Garrett M. Frampton, Siraj M. Ali, Samuel M. Rubinstein, David Fabrizio, Jeffrey S. Ross, Sohail Balasubramanian, Vincent A. Miller, Philip J. Stephens, Jeffrey A. Sosman, Christine M. Lovly

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAFV 600-mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pretreatment and progression biopsies from a patient who progressed on dabrafenib and trametinib. In addition to a preserved BRAFV 600E mutation, an internal deletion (rearrangement) of BRAF was observed in the progression sample. This deletion involved exons 2–8, which includes the Ras-binding domain, and is analogous to previously documented BRAF fusions and splice variants known to reactivate RAS-RAF-MEK-ERK signaling. In a large cohort of melanomas, 10 additional internal deletions were identified (0.4% of all melanomas; nine of which had concurrent BRAF mutations), as well as sporadically in other tumor types. Thus, we describe a novel mechanism of resistance to BRAF and MEK inhibition.

Original languageEnglish (US)
Pages (from-to)432-436
Number of pages5
JournalPigment Cell and Melanoma Research
Issue number3
StatePublished - May 2018


  • BRAF
  • dabrafenib
  • internal deletion
  • rearrangement
  • resistance
  • trametinib
  • vemurafenib

ASJC Scopus subject areas

  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Dermatology


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