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Isolation of Human Endothelial Cells from Normal Colon and Colorectal Carcinoma - An Improved Protocol
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BRAFV600E mutation: A promising target in colorectal neuroendocrine carcinoma

Levent Dizdar1, Thomas A Werner1, Jasmin C Drusenheimer2

  • 1Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.

International Journal of Cancer
|August 26, 2018
PubMed

Insights

The BRAFV600E mutation is present in nearly half of colorectal neuroendocrine carcinomas (NECs), driving tumor growth. Targeting BRAF and MEK with drugs like dabrafenib and trametinib effectively inhibits BRAFV600E-mutated NEC growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) encompasses a spectrum of tumors, including highly aggressive gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC).
  • The role of BRAFV600E mutation and mitogen-activated protein kinase (MAPK) signaling in GEP-NEN, particularly GEP-NEC, remains incompletely understood.
  • Understanding these pathways is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the frequency and significance of the BRAFV600E mutation in GEP-NEN.
  • To explore the role of MAPK signaling, specifically MEK phosphorylation (pMEK), in relation to BRAFV600E.
  • To evaluate the therapeutic potential of BRAF and MEK inhibitors in BRAFV600E-mutated GEP-NEC.

Main Methods:

  • Sanger sequencing of BRAF exon 15 was performed on 71 primary GEP-NEN samples.
  • Immunohistochemistry was used to assess MEK phosphorylation (pMEK) levels.
  • In vitro and in vivo studies using GEP-NEC cell lines and xenografts were conducted to assess the effects of BRAF and MEK inhibition.

Main Results:

  • BRAFV600E mutation was found in 9.9% of all GEP-NENs, with a significantly higher frequency (46.7%) in colorectal NECs.
  • BRAFV600E mutation correlated with elevated pMEK levels and advanced tumor stages.
  • Pharmacological inhibition of BRAF and MEK effectively reduced GEP-NEC cell proliferation, induced cell cycle arrest, and promoted apoptosis exclusively in BRAFV600E-mutated cells and xenografts.

Conclusions:

  • The BRAFV600E mutation is a key driver in a subset of aggressive colorectal NECs.
  • Targeting the BRAF/MEK pathway with specific inhibitors demonstrates significant therapeutic efficacy in preclinical models of BRAFV600E-mutated GEP-NEC.
  • BRAF and MEK-directed therapy represents a promising treatment strategy for patients with BRAF mutant colorectal NECs.
Keywords:
BRAFV600EGEP-NECcolorectal NECdabrafenibtrametinibvemurafenib

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