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

 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 
 ONCOGENE, Vol.36(23) : 3334-3345, 2017 
Journal Title
Issue Date
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
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.
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1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Eun Kyung(김은경)
Kim, Han Sang(김한상) ORCID logo https://orcid.org/0000-0002-6504-9927
Shin, Sang Joon(신상준) ORCID logo https://orcid.org/0000-0001-5350-7241
Chung, Kee Yang(정기양) ORCID logo https://orcid.org/0000-0003-3257-0297
Jung, Min Kyu(정민규) ORCID logo https://orcid.org/0000-0001-8281-3387
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
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