1. Academic Validation
  2. BRAFV600E mutation: A promising target in colorectal neuroendocrine carcinoma

BRAFV600E mutation: A promising target in colorectal neuroendocrine carcinoma

  • Int J Cancer. 2019 Mar 15;144(6):1379-1390. doi: 10.1002/ijc.31828.
Levent Dizdar 1 Thomas A Werner 1 Jasmin C Drusenheimer 2 Birte Möhlendick 1 Katharina Raba 3 Inga Boeck 4 Martin Anlauf 4 Matthias Schott 5 Wolfgang Göring 2 Irene Esposito 2 Nikolas H Stoecklein 1 Wolfram T Knoefel 1 Andreas Krieg 1
Affiliations

Affiliations

  • 1 Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
  • 2 Institute of Pathology, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
  • 3 Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
  • 4 Institute of Pathology and Cytology, St. Vincenz Hospital Limburg, Limburg, Germany.
  • 5 Division for Specific Endocrinology, Medical Faculty, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
Abstract

To determine the role of BRafV600E mutation and MAPK signaling as well as the effects of BRaf and MEK directed therapy in gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN), with a focus on highly aggressive gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Using Sanger sequencing of BRaf exon 15 we determined the frequency of BRafV600E mutations in 71 primary GEP-NENs. MEK phosphorylation was examined by immunohistochemistry in corresponding tissue samples. To evaluate the biological relevance of BRafV600E mutation and MAPK signaling in GEP-NECs, effects of a pharmacological BRaf and MEK inhibition were analyzed in NEC cell lines both in vitro and in vivo. BRafV600E mutation was detected in 9.9% of all GEP-NENs. Interestingly, only NECs of the colon harbored BRafV600E mutations, leading to a mutation frequency of 46.7% in this subgroup of patients. In addition, a BRafV600E mutation was significantly associated with high levels of MEK phosphorylation (pMEK) and advanced tumor stages. Pharmacological inhibition of BRaf and MEK abrogated NEC cell growth, inducing G1 cell cycle arrest and Apoptosis only in BRafV600E mutated cells. BRaf Inhibitor dabrafenib and MEK Inhibitor trametinib prevented growth of BRafV600E positive NEC xenografts. High frequencies of BRafV600E mutation and elevated expression levels of pMEK were detected in biologically aggressive and highly proliferative colorectal NECs. We provide evidence that targeting BRaf oncogene may represent a therapeutic strategy for patients with BRaf mutant colorectal NECs.

Keywords

BRAFV600E; GEP-NEC; colorectal NEC; dabrafenib; trametinib; vemurafenib.

Figures
Products