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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

Oncogene volume 36, pages 3334–3345 (2017)Cite this article

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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.

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Acknowledgements

This study was supported in part by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning (2014R1A1A1004823 to M Jung), and the NRF by the Korean government (MEST; 2012R1A2A2A01046927 to B Cho). The results of the analysis of mutation frequencies in cutaneous melanomas compared with corresponding frequencies in PMM were based on TCGA Research Network generated data (http://cancergenome.nih.gov/).

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Author notes

  1. H S Kim, M Jung and H N Kang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

    H S Kim, M Jung, S J Shin & B C Cho

  2. Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea

    H S Kim

  3. JEUK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea

    H N Kang, H Kim, C-W Park, S-M Kim, S G Kim & M R Yun

  4. Department of Pathology, Yonsei University College of Medicine, Seoul, Korea

    S H Kim & E K Kim

  5. Anatomic Pathology Reference Lab, Seegene Medical Foundation, Seoul, Korea

    S H Kim

  6. Department of Dermatology, Yanbian University Hospital, Yanji City, China

    Z Zheng

  7. Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea

    K Y Chung

  8. Foundation Medicine Inc., Cambridge, MA, USA

    J Greenbowe & S M Ali

  9. Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea

    T-M Kim

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Correspondence to S M Ali, T-M Kim or B C Cho.

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Kim, H., Jung, M., Kang, H. et al. Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition. Oncogene 36, 3334–3345 (2017). https://doi.org/10.1038/onc.2016.486

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