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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

DC FieldValueLanguage
dc.contributor.author김은경-
dc.contributor.author김한상-
dc.contributor.author신상준-
dc.contributor.author정기양-
dc.contributor.author정민규-
dc.contributor.author조병철-
dc.date.accessioned2018-07-20T08:06:57Z-
dc.date.available2018-07-20T08:06:57Z-
dc.date.issued2017-
dc.identifier.issn0950-9232-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/160849-
dc.description.abstractDespite 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.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherNature Publishing Group-
dc.relation.isPartOfOncogene-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rightshttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAnimals-
dc.subject.MESHAntineoplastic Agents/pharmacology-
dc.subject.MESHApoptosis/drug effects-
dc.subject.MESHBiomarkers, Tumor/genetics-
dc.subject.MESHBiomarkers, Tumor/metabolism-
dc.subject.MESHCell Proliferation/drug effects-
dc.subject.MESHCyclin-Dependent Kinase 4/antagonists & inhibitors-
dc.subject.MESHCyclin-Dependent Kinase 4/genetics-
dc.subject.MESHCyclin-Dependent Kinase 4/metabolism-
dc.subject.MESHCyclin-Dependent Kinase 6/antagonists & inhibitors-
dc.subject.MESHCyclin-Dependent Kinase 6/genetics-
dc.subject.MESHCyclin-Dependent Kinase 6/metabolism-
dc.subject.MESHFemale-
dc.subject.MESHHumans-
dc.subject.MESHMAP Kinase Kinase 1/antagonists & inhibitors-
dc.subject.MESHMAP Kinase Kinase 1/genetics-
dc.subject.MESHMAP Kinase Kinase 1/metabolism-
dc.subject.MESHMelanoma/drug therapy-
dc.subject.MESHMelanoma/metabolism-
dc.subject.MESHMelanoma/pathology-
dc.subject.MESHMice-
dc.subject.MESHMice, Nude-
dc.subject.MESHMitogen-Activated Protein Kinases/metabolism-
dc.subject.MESHMucous Membrane/drug effects-
dc.subject.MESHMucous Membrane/metabolism-
dc.subject.MESHMucous Membrane/pathology-
dc.subject.MESHOncogene Proteins, Fusion/genetics-
dc.subject.MESHOncogene Proteins, Fusion/metabolism-
dc.subject.MESHPhosphatidylinositol 3-Kinases/antagonists & inhibitors-
dc.subject.MESHPhosphatidylinositol 3-Kinases/genetics-
dc.subject.MESHPhosphatidylinositol 3-Kinases/metabolism-
dc.subject.MESHProto-Oncogene Proteins B-raf/genetics-
dc.subject.MESHProto-Oncogene Proteins B-raf/metabolism-
dc.subject.MESHSkin Neoplasms/drug therapy-
dc.subject.MESHSkin Neoplasms/metabolism-
dc.subject.MESHSkin Neoplasms/pathology-
dc.subject.MESHTranscription Factors/genetics-
dc.subject.MESHTranscription Factors/metabolism-
dc.subject.MESHTumor Cells, Cultured-
dc.subject.MESHXenograft Model Antitumor Assays-
dc.titleOncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine-
dc.contributor.departmentDept. of Pathology-
dc.contributor.googleauthorH S Kim-
dc.contributor.googleauthorM Jung-
dc.contributor.googleauthorH N Kang-
dc.contributor.googleauthorH Kim-
dc.contributor.googleauthorC-W Park-
dc.contributor.googleauthorS-M Kim-
dc.contributor.googleauthorS J Shin-
dc.contributor.googleauthorS H Kim-
dc.contributor.googleauthorS G Kim-
dc.contributor.googleauthorE K Kim-
dc.contributor.googleauthorM R Yun-
dc.contributor.googleauthorZ Zheng-
dc.contributor.googleauthorK Y Chung-
dc.contributor.googleauthorJ Greenbowe-
dc.contributor.googleauthorS M Ali-
dc.contributor.googleauthorT-M Kim-
dc.identifier.doi10.1038/onc.2016.486-
dc.contributor.localIdA04868-
dc.contributor.localIdA01098-
dc.contributor.localIdA02105-
dc.contributor.localIdA03582-
dc.contributor.localIdA03606-
dc.contributor.localIdA03822-
dc.relation.journalcodeJ02413-
dc.identifier.eissn1476-5594-
dc.identifier.pmid28092667-
dc.identifier.urlhttp://www.nature.com/articles/onc2016486-
dc.contributor.alternativeNameKim, Eun Kyung-
dc.contributor.alternativeNameKim, Han Sang-
dc.contributor.alternativeNameShin, Sang Joon-
dc.contributor.alternativeNameChung, Kee Yang-
dc.contributor.alternativeNameJung, Min Kyu-
dc.contributor.alternativeNameCho, Byoung Chul-
dc.contributor.affiliatedAuthorKim, Eun Kyung-
dc.contributor.affiliatedAuthorKim, Han Sang-
dc.contributor.affiliatedAuthorShin, Sang Joon-
dc.contributor.affiliatedAuthorChung, Kee Yang-
dc.contributor.affiliatedAuthorJung, Min Kyu-
dc.contributor.affiliatedAuthorCho, Byoung Chul-
dc.citation.volume36-
dc.citation.number23-
dc.citation.startPage3334-
dc.citation.endPage3345-
dc.identifier.bibliographicCitationOncogene, Vol.36(23) : 3334-3345, 2017-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers

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