BRAFV600E mutation: A promising target in colorectal neuroendocrine carcinoma. Issue 6 (30th October 2018)

• Record Type: Journal Article
• Authors: Dizdar, Levent; Werner, Thomas A.; Drusenheimer, Jasmin C.; Möhlendick, Birte; Raba, Katharina; Boeck, Inga; Anlauf, Martin; Schott, Matthias; Göring, Wolfgang; Esposito, Irene; Stoecklein, Nikolas H.; Knoefel, Wolfram T.; Krieg, Andreas
• Is Part Of: International journal of cancer. Volume 144:Issue 6(2019)
• Page Start: 1379
• Page End: 1390
• Publication Date: 2018-10-30
• Subjects: GEP‐NEC -- BRAFV600E -- colorectal NEC -- vemurafenib -- dabrafenib -- trametinib; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31828
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : To determine the role of BRAF V600E 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 BRAF V600E mutations in 71 primary GEP‐NENs. MEK phosphorylation was examined by immunohistochemistry in corresponding tissue samples. To evaluate the biological relevance of BRAF V600E 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. BRAF V600E mutation was detected in 9.9% of all GEP‐NENs. Interestingly, only NECs of the colon harbored BRAF V600E mutations, leading to a mutation frequency of 46.7% in this subgroup of patients. In addition, a BRAF V600E 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 BRAF V600E mutated cells. BRAF inhibitor dabrafenib and MEK inhibitor trametinib prevented growth of BRAF V600E positive NEC xenografts. High frequencies of BRAF V600E 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. Abstract : What's new? Mutation of the BRAF gene at amino acid position 600, producing the BRAF V600E variant, is an established oncogenic driver in different malignant tumors. In this study, high frequencies of the BRAF V600E mutation, along with elevated levels of phosphorylated MEK, were detected in colorectal neuroendocrine carcinomas (NECs). BRAF V600E mutation was significantly associated with advanced tumor stage. Growth of BRAF V600E ‐positive NEC xenografts was impeded by treatment with either the BRAF inhibitor dabrafenib or the MEK inhibitor trametinib. The data highlight the biological relevance of BRAF/MEK signaling in NEC and support further clinical evaluation of BRAF‐ and MEK‐directed therapy for colorectal NEC.