BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy

Pigment Cell Melanoma Res. 2018 May;31(3):432-436. doi: 10.1111/pcmr.12674. Epub 2017 Dec 16.


BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAFV600 -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 BRAFV600E 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.

Keywords: BRAF; dabrafenib; internal deletion; rearrangement; resistance; trametinib; vemurafenib.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Substitution
  • Base Sequence*
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Imidazoles / therapeutic use*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Melanoma* / drug therapy
  • Melanoma* / enzymology
  • Melanoma* / genetics
  • Mutation, Missense*
  • Oximes / therapeutic use*
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins B-raf* / genetics
  • Proto-Oncogene Proteins B-raf* / metabolism
  • Pyridones / therapeutic use*
  • Pyrimidinones / therapeutic use*
  • Sequence Deletion*


  • Imidazoles
  • Oximes
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • trametinib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • dabrafenib