双特异性蛋白磷酸酶 DUSP4 调节 BRAF 野生型黑色素瘤对 MEK 抑制的反应。
Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma.
机构信息
Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
Department of Oncology, Old Road Campus Research Building, University of Oxford, Oxford, UK.
出版信息
Br J Cancer. 2020 Feb;122(4):506-516. doi: 10.1038/s41416-019-0673-5. Epub 2019 Dec 16.
BACKGROUND
Aiming to improve treatment options for BRAF wild-type melanoma, we previously conducted the DOC-MEK study of docetaxel with MEK inhibitor (MEKi) selumetinib or placebo, revealing trends to prolongation of progression-free survival (hazard ratio 0.75, P = 0.130), and improved response rates (32% vs 14%, P = 0.059) with docetaxel plus selumetinib. NRAS status did not associate with outcome. Here, the aim was to identify novel biomarkers of response to MEKi.
METHODS
A MEK 6 gene signature was quantified using NanoString and correlated with clinical outcomes. Two components of the gene signature were investigated by gene silencing in BRAF/NRAS wild-type melanoma cells.
RESULTS
In melanomas of patients on the selumetinib but not the placebo arm, two gene signature components, dual-specificity protein phosphatase 4 (DUSP4) and ETS translocation variant 4 (ETV4), were expressed more highly in responders than non-responders. In vitro, ETV4 depletion inhibited cell survival but did not influence sensitivity to MEKi selumetinib or trametinib. In contrast, DUSP4-depleted cells showed enhanced cell survival and increased resistance to both selumetinib and trametinib.
CONCLUSIONS
ETV4 and DUSP4 associated with clinical response to docetaxel plus selumetinib. DUSP4 depletion induced MEKi resistance, suggesting that DUSP4 is not only a biomarker but also a mediator of MEKi sensitivity.
CLINICAL TRIAL REGISTRATION
DOC-MEK (EudraCT no: 2009-018153-23).
背景
为了改善 BRAF 野生型黑色素瘤的治疗选择，我们之前进行了 DOC-MEK 研究，即在多西他赛中加入 MEK 抑制剂（MEKi）selumetinib 或安慰剂，结果显示多西他赛联合 selumetinib可延长无进展生存期（风险比 0.75，P=0.130）和提高缓解率（32%比 14%，P=0.059），但 NRAS 状态与结局无关。在此，目的是确定 MEKi 反应的新生物标志物。
方法
使用 NanoString 定量测定 MEK 6 基因谱，并将其与临床结局相关联。通过基因沉默法在 BRAF/NRAS 野生型黑色素瘤细胞中研究基因谱的两个组成部分。
结果
在接受 selumetinib 而非安慰剂治疗的患者的黑色素瘤中，两个基因谱组成部分，双特异性蛋白磷酸酶 4（DUSP4）和 ETS 易位变体 4（ETV4），在缓解者中的表达高于非缓解者。在体外，ETV4 耗竭抑制细胞存活，但不影响对 MEKi selumetinib 或 trametinib 的敏感性。相反，DUSP4 耗竭的细胞显示出增强的细胞存活和对 selumetinib 和 trametinib 的增加的耐药性。
结论
ETV4 和 DUSP4 与多西他赛联合 selumetinib 的临床反应相关。DUSP4 耗竭诱导 MEKi 耐药性，表明 DUSP4 不仅是一个生物标志物，也是 MEKi 敏感性的介导物。
临床试验注册
DOC-MEK（EudraCT 编号：2009-018153-23）。
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