Identification of coexistence of BRAF V600E mutation and EZH2 gain specifically in melanoma as a promising target for combination therapy

Journal of Translational Medicine

Research

Yan Kong¹  Jun Guo¹  Junya Yan²  Xiaowen Wu²  Longwen Xu²  Huan Tang²  Bin Lian²  Huan Yu²  Jie Dai²  Tianxiao Xu²  Chuanliang Cui²  Jiayi Yu²  Lili Mao²  Siming Li²  Zhihong Chi²  Meng Ma² 

[1] Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, 100142, Beijing, China;The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China;

关键词: EZH2;    BRAF V600E;    Combination therapy;    Melanoma;   

DOI  :  10.1186/s12967-017-1344-z

 received in 2017-07-24, accepted in 2017-11-12,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundCoexistence of enhancer of zeste homolog 2 (EZH2) and BRAF gene aberrations has been described in many cancer types. In this study, we aim to explore the coexistence status of BRAF V600E mutation and the copy number variation of EZH2 and explore the potential of this combination as a therapeutic target.MethodsA total of 138 cases of melanoma samples harboring BRAF V600E mutation were included, and EZH2 copy numbers were examined by QuantiGenePlex DNA Assays. Clinical pathological distinction between patient groups with or without EZH2 amplification (hereafter referred to as EZH2 gain) was statistically analyzed. The sensitivity of melanoma cell lines and patient-derived xenograft (PDX) models containing BRAF V600E mutation with or without EZH2 gain to vemurafenib (BRAF inhibitor), GSK2816126 (EZH2 inhibitor) and a combination of both agents was evaluated.ResultsIn our cohort, the coexistence rate of BRAF V600E mutation and EZH2 gain was up to 29.0%, and significant differences in overall survival and disease-free survival were found between no EZH2 copy number gain and gain groups (P = 0.038, P = 0.030), gain and high EZH2 copy number gain groups (P = 0.006, P = 0.010). Combination with BRAF and EZH2 inhibition showed better inhibitory efficacy in melanoma prevention compared with vemurafenib monotherapy. More importantly, this improved therapeutic effect was observed especially in melanoma cell lines and PDX models containing concurrently BRAF V600E mutation and EZH2 gain.ConclusionsCoexistence of BRAF V600E mutation and EZH2 gain is rather prevalent in melanoma. Our findings provided evidence for the feasibility of combination therapy with EZH2 and BRAF inhibitors in melanoma with concurrent BRAF V600E mutation and EZH2 gain.

【 授权许可】

CC BY   
© The Author(s) 2017