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

Authors: Allen, A.; Qin, A. C. R.; Raj, N.; Wang, J.; Uddin, S.; Yao, Z.; Tang, L.; Meyers, P. A.; Taylor, B. S.; Berger, M. F.; Yaeger, R.; Reidy-Lagunes, D.; Pratilas, C. A.
Article Title: Rare BRAF mutations in pancreatic neuroendocrine tumors may predict response to RAF and MEK inhibition
Abstract: 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. © 2019 Allen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Journal Title: PLoS ONE
Volume: 14
Issue: 6
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2019-06-03
Start Page: e0217399
Language: English
DOI: 10.1371/journal.pone.0217399
PUBMED: 31158244
PROVIDER: scopus
PMCID: PMC6546234
Notes: Source: Scopus
Citation Impact
MSK Authors
  1. Diane Lauren Reidy
    230 Reidy
  2. Rona Denit Yaeger
    164 Yaeger
  3. Laura Hong Tang
    382 Tang
  4. Michael Forman Berger
    570 Berger
  5. Paul Meyers
    287 Meyers
  6. Barry Stephen Taylor
    226 Taylor
  7. Zhan Yao
    37 Yao
  8. Nitya Prabhakar Raj
    59 Raj
  9. Sharmeen Yeasmin Uddin
    5 Uddin