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

Huan Yu,Bin Lian,Jie Dai,Longwen Xu,Lili Mao,Meng Ma,Chuanliang Cui,Yan Kong,Jiayi Yu,Zhihong Chi,Xiaowen Wu,Siming Li,Huan Tang,Tianxiao Xu,Jun Guo,Junya Yan

doi:10.1186/s12967-017-1344-z

Abstract

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.

Highlights

Coexistence of enhancer of zeste homolog 2 (EZH2) and BRAF gene aberrations has been described in many cancer types
Our data suggested that the coexistence of EZH2 gain and the BRAF V600E mutation was prevalent in melanoma, especially mucosal subtype
Significant differences in overall survival and disease-free survival were found between no EZH2 copy number gain and gain groups (P = 0.038, hazard ratios (HRs) 0.50, 95% combination index (CI) 0.02–0.61; P = 0.030, HR 0.49, 95% CI 0.26–0.94), gain and high EZH2 copy number gain groups (P = 0.006, P = 0.010) (OS median value: no gain group: 78.1 months; gain group: 40.8 months; high gain group: 31.3 months; DFS median value: no gain group: 39.5 months; gain group: 22.3 months; high gain group: 11.1 months) (Fig. 1b)

Summary

Introduction

Coexistence of enhancer of zeste homolog 2 (EZH2) and BRAF gene aberrations has been described in many cancer types. 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. Vemurafenib, a BRAF inhibitor, has been shown to improve outcomes in the majority of melanoma patients harbouring BRAF V600E mutation, with a median overall survival (OS) of approximately 16 months [4]. Despite rapid early response and high response rate to these combination therapeutic regimens, progression of disease occurs at a median of 11 months, with few patients remaining progression-free beyond 15 months [16], novel combination targets are urgently needed to be found

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