Cited 71 times in
Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition
DC Field | Value | Language |
---|---|---|
dc.contributor.author | 김은경 | - |
dc.contributor.author | 김한상 | - |
dc.contributor.author | 신상준 | - |
dc.contributor.author | 정기양 | - |
dc.contributor.author | 정민규 | - |
dc.contributor.author | 조병철 | - |
dc.date.accessioned | 2018-07-20T08:06:57Z | - |
dc.date.available | 2018-07-20T08:06:57Z | - |
dc.date.issued | 2017 | - |
dc.identifier.issn | 0950-9232 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/160849 | - |
dc.description.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. | - |
dc.description.statementOfResponsibility | restriction | - |
dc.language | English | - |
dc.publisher | Nature Publishing Group | - |
dc.relation.isPartOf | ONCOGENE | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.rights | https://creativecommons.org/licenses/by-nc-nd/2.0/kr/ | - |
dc.subject.MESH | Animals | - |
dc.subject.MESH | Antineoplastic Agents/pharmacology | - |
dc.subject.MESH | Apoptosis/drug effects | - |
dc.subject.MESH | Biomarkers, Tumor/genetics | - |
dc.subject.MESH | Biomarkers, Tumor/metabolism | - |
dc.subject.MESH | Cell Proliferation/drug effects | - |
dc.subject.MESH | Cyclin-Dependent Kinase 4/antagonists & inhibitors | - |
dc.subject.MESH | Cyclin-Dependent Kinase 4/genetics | - |
dc.subject.MESH | Cyclin-Dependent Kinase 4/metabolism | - |
dc.subject.MESH | Cyclin-Dependent Kinase 6/antagonists & inhibitors | - |
dc.subject.MESH | Cyclin-Dependent Kinase 6/genetics | - |
dc.subject.MESH | Cyclin-Dependent Kinase 6/metabolism | - |
dc.subject.MESH | Female | - |
dc.subject.MESH | Humans | - |
dc.subject.MESH | MAP Kinase Kinase 1/antagonists & inhibitors | - |
dc.subject.MESH | MAP Kinase Kinase 1/genetics | - |
dc.subject.MESH | MAP Kinase Kinase 1/metabolism | - |
dc.subject.MESH | Melanoma/drug therapy | - |
dc.subject.MESH | Melanoma/metabolism | - |
dc.subject.MESH | Melanoma/pathology | - |
dc.subject.MESH | Mice | - |
dc.subject.MESH | Mice, Nude | - |
dc.subject.MESH | Mitogen-Activated Protein Kinases/metabolism | - |
dc.subject.MESH | Mucous Membrane/drug effects | - |
dc.subject.MESH | Mucous Membrane/metabolism | - |
dc.subject.MESH | Mucous Membrane/pathology | - |
dc.subject.MESH | Oncogene Proteins, Fusion/genetics | - |
dc.subject.MESH | Oncogene Proteins, Fusion/metabolism | - |
dc.subject.MESH | Phosphatidylinositol 3-Kinases/antagonists & inhibitors | - |
dc.subject.MESH | Phosphatidylinositol 3-Kinases/genetics | - |
dc.subject.MESH | Phosphatidylinositol 3-Kinases/metabolism | - |
dc.subject.MESH | Proto-Oncogene Proteins B-raf/genetics | - |
dc.subject.MESH | Proto-Oncogene Proteins B-raf/metabolism | - |
dc.subject.MESH | Skin Neoplasms/drug therapy | - |
dc.subject.MESH | Skin Neoplasms/metabolism | - |
dc.subject.MESH | Skin Neoplasms/pathology | - |
dc.subject.MESH | Transcription Factors/genetics | - |
dc.subject.MESH | Transcription Factors/metabolism | - |
dc.subject.MESH | Tumor Cells, Cultured | - |
dc.subject.MESH | Xenograft Model Antitumor Assays | - |
dc.title | Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition | - |
dc.type | Article | - |
dc.contributor.college | College of Medicine | - |
dc.contributor.department | Dept. of Pathology | - |
dc.contributor.googleauthor | H S Kim | - |
dc.contributor.googleauthor | M Jung | - |
dc.contributor.googleauthor | H N Kang | - |
dc.contributor.googleauthor | H Kim | - |
dc.contributor.googleauthor | C-W Park | - |
dc.contributor.googleauthor | S-M Kim | - |
dc.contributor.googleauthor | S J Shin | - |
dc.contributor.googleauthor | S H Kim | - |
dc.contributor.googleauthor | S G Kim | - |
dc.contributor.googleauthor | E K Kim | - |
dc.contributor.googleauthor | M R Yun | - |
dc.contributor.googleauthor | Z Zheng | - |
dc.contributor.googleauthor | K Y Chung | - |
dc.contributor.googleauthor | J Greenbowe | - |
dc.contributor.googleauthor | S M Ali | - |
dc.contributor.googleauthor | T-M Kim | - |
dc.identifier.doi | 10.1038/onc.2016.486 | - |
dc.contributor.localId | A04868 | - |
dc.contributor.localId | A01098 | - |
dc.contributor.localId | A02105 | - |
dc.contributor.localId | A03582 | - |
dc.contributor.localId | A03606 | - |
dc.contributor.localId | A03822 | - |
dc.relation.journalcode | J02413 | - |
dc.identifier.eissn | 1476-5594 | - |
dc.identifier.pmid | 28092667 | - |
dc.identifier.url | http://www.nature.com/articles/onc2016486 | - |
dc.contributor.alternativeName | Kim, Eun Kyung | - |
dc.contributor.alternativeName | Kim, Han Sang | - |
dc.contributor.alternativeName | Shin, Sang Joon | - |
dc.contributor.alternativeName | Chung, Kee Yang | - |
dc.contributor.alternativeName | Jung, Min Kyu | - |
dc.contributor.alternativeName | Cho, Byoung Chul | - |
dc.contributor.affiliatedAuthor | Kim, Eun Kyung | - |
dc.contributor.affiliatedAuthor | Kim, Han Sang | - |
dc.contributor.affiliatedAuthor | Shin, Sang Joon | - |
dc.contributor.affiliatedAuthor | Chung, Kee Yang | - |
dc.contributor.affiliatedAuthor | Jung, Min Kyu | - |
dc.contributor.affiliatedAuthor | Cho, Byoung Chul | - |
dc.citation.volume | 36 | - |
dc.citation.number | 23 | - |
dc.citation.startPage | 3334 | - |
dc.citation.endPage | 3345 | - |
dc.identifier.bibliographicCitation | ONCOGENE, Vol.36(23) : 3334-3345, 2017 | - |
dc.identifier.rimsid | 60733 | - |
dc.type.rims | ART | - |
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