0 22

Cited 0 times in

Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition

Authors
 H S Kim  ;  M Jung  ;  H N Kang  ;  H Kim  ;  C-W Park  ;  S-M Kim  ;  S J Shin  ;  S H Kim  ;  S G Kim  ;  E K Kim  ;  M R Yun  ;  Z Zheng  ;  K Y Chung  ;  J Greenbowe  ;  S M Ali  ;  T-M Kim 
Citation
 Oncogene, Vol.36(23) : 3334-3345, 2017 
Journal Title
 Oncogene 
ISSN
 0950-9232 
Issue Date
2017
MeSH
Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase 4/antagonists & inhibitors ; Cyclin-Dependent Kinase 4/genetics ; Cyclin-Dependent Kinase 4/metabolism ; Cyclin-Dependent Kinase 6/antagonists & inhibitors ; Cyclin-Dependent Kinase 6/genetics ; Cyclin-Dependent Kinase 6/metabolism ; Female ; Humans ; MAP Kinase Kinase 1/antagonists & inhibitors ; MAP Kinase Kinase 1/genetics ; MAP Kinase Kinase 1/metabolism ; Melanoma/drug therapy ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Mice, Nude ; Mitogen-Activated Protein Kinases/metabolism ; Mucous Membrane/drug effects ; Mucous Membrane/metabolism ; Mucous Membrane/pathology ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; Skin Neoplasms/drug therapy ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Abstract
Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated. We biologically characterized a novel ZNF767-BRAF fusion found in a vemurafenib-refractory respiratory tract PMM, from which cell line harboring ZNF767-BRAF fusion were established for further molecular analyses. In an independent data set, NFIC-BRAF fusion was identified in an oral PMM case and TMEM178B-BRAF fusion and DGKI-BRAF fusion were identified in two malignant melanomas with a low mutational burden (number of mutation per megabase, 0.8 and 4, respectively). Subsequent analyses revealed that the ZNF767-BRAF fusion protein promotes RAF dimerization and activation of the MAPK pathway. We next tested the in vitro and in vivo efficacy of vemurafenib, trametinib, BKM120 or LEE011 alone and in combination. Trametinib effectively inhibited tumor cell growth in vitro, but the combination of trametinib and BKM120 or LEE011 yielded more than additive anti-tumor effects both in vitro and in vivo in a melanoma cells harboring the BRAF fusion. In conclusion, BRAF fusions define a new molecular subset of PMM that can be targeted therapeutically by the combination of a MEK inhibitor with PI3K or cyclin-dependent kinase 4/6 inhibitors.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/160849
DOI
10.1038/onc.2016.486
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실)
Yonsei Authors
김은경(Kim, Eun Kyung) ; 김한상(Kim, Han Sang) ; 신상준(Shin, Sang Joon) ; 정기양(Chung, Kee Yang) ; 정민규(Jung, Min Kyu) ; 조병철(Cho, Byoung Chul)
사서에게 알리기
  feedback
Full Text
http://www.nature.com/articles/onc2016486
Export
RIS (EndNote)
XLS (Excel)
XML

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse