Rare BRAF mutations in pancreatic neuroendocrine tumors may predict response to RAF and MEK inhibition

PLoS One. 2019 Jun 3;14(6):e0217399. doi: 10.1371/journal.pone.0217399. eCollection 2019.


The clinical significance of BRAF alterations in well-differentiated (WD) metastatic pancreatic neuroendocrine tumor (panNET) is unknown, but BRAF-mutated panNET could represent a subset characterized by an identifiable and clinically actionable driver. Following the identification of two patients with WD metastatic panNET whose tumors harbored BRAF mutations, we queried the MSK-IMPACT series of 80 patients with WD metastatic panNET for additional mutations in BRAF, and in other genes involved in RAS/ RTK/ PI3K signaling pathways. BRAF mutations were identified in six samples (7.5%): two tumors harbored V600E mutations, one tumor each expressed K601E, T599K, and T310I mutations, and one tumor expressed both G596D and E451K BRAF. Few additional actionable driver alterations were identified. To determine the ERK activating capability of four BRAF mutations not previously characterized, mutant constructs were tested in model systems. Biochemical characterization of BRAF mutations revealed both high and low activity mutants. Engineered cells expressing BRAF K601E and V600E were used for in vitro drug testing of RAF and MEK inhibitors currently in clinical use. BRAF K601E demonstrated reduced sensitivity to dabrafenib compared to BRAF V600E, but the combination of RAF plus MEK inhibition was effective in cells expressing this mutation. Herein, we describe the clinical course of a patient with BRAF K601E and a patient with BRAF V600E WD metastatic panNET, and the identification of four mutations in BRAF not previously characterized. The combined clinical and biochemical data support a potential role for RAF and MEK inhibitors, or a combination of these, in a selected panNET population.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Cell Line, Tumor
  • Humans
  • Imidazoles / pharmacology*
  • MAP Kinase Kinase Kinases* / antagonists & inhibitors
  • MAP Kinase Kinase Kinases* / genetics
  • MAP Kinase Kinase Kinases* / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Mutation, Missense*
  • NIH 3T3 Cells
  • Neoplasm Metastasis
  • Neuroendocrine Tumors* / drug therapy
  • Neuroendocrine Tumors* / enzymology
  • Neuroendocrine Tumors* / genetics
  • Neuroendocrine Tumors* / pathology
  • Oximes / pharmacology*
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / enzymology
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins B-raf* / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf* / genetics
  • Proto-Oncogene Proteins B-raf* / metabolism


  • Imidazoles
  • Oximes
  • Protein Kinase Inhibitors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase Kinases
  • dabrafenib