title: Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition.
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.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.|Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: H S
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: M
authors.initials: M
authors.lastname: Jung
authors.affiliation: JEUK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: H N
authors.initials: HN
authors.lastname: Kang
authors.affiliation: JEUK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.affiliation: JEUK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: C-W
authors.initials: CW
authors.lastname: Park
authors.affiliation: JEUK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: S-M
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: S J
authors.initials: SJ
authors.lastname: Shin
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.|Anatomic Pathology Reference Lab, Seegene Medical Foundation, Seoul, Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: JEUK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: S G
authors.initials: SG
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: E K
authors.initials: EK
authors.lastname: Kim
authors.affiliation: JEUK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea.
authors.forename: M R
authors.initials: MR
authors.lastname: Yun
authors.affiliation: Department of Dermatology, Yanbian University Hospital, Yanji City, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: K Y
authors.initials: KY
authors.lastname: Chung
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Greenbowe
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: T-M
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: B C
authors.initials: BC
authors.lastname: Cho
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D048369:MAP Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D014157:Transcription Factors; C000622467:ZNF778 protein, human; C482119:BRAF protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human