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Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma.

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。

  • 影响因子:5.52
  • DOI:10.1038/s41416-019-0673-5
  • 作者列表:"Gupta A","Towers C","Willenbrock F","Brant R","Hodgson DR","Sharpe A","Smith P","Cutts A","Schuh A","Asher R","Myers K","Love S","Collins L","Wise A","Middleton MR","Macaulay VM
  • 发表时间:2020-02-01
Abstract

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).

摘要

背景: 为了改善 BRAF 野生型黑色素瘤的治疗选择,我们以前进行了多西他赛与 MEK 抑制剂 (MEKi) selumetinib 或安慰剂的 DOC-MEK 研究, 揭示了延长无进展生存期的趋势 (风险比 0.75,p = 0.130),以及多西他赛加 selumetinib 改善的缓解率 (32% vs 14%,p = 0.059)。NRAS 状态与结局无关。这里,目的是确定对 MEKi 反应的新型生物标志物。 方法: 使用 NanoString 对 MEK 6 基因标记进行定量,并与临床结局相关。通过 BRAF/NRAS 野生型黑色素瘤细胞中的基因沉默研究了基因标记的两种成分。 结果: 在 selumetinib 而非安慰剂组患者的黑色素瘤中,两个基因标记成分,双特异性蛋白磷酸酶 4 (DUSP4) 和 ETS 易位变异体 4 (ETV4), 在应答者中的表达高于非应答者。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。相比之下,DUSP4-depleted 细胞显示出增强的细胞存活和增加对 selumetinib 和 trametinib 的耐药性。 结论: ETV4 和 DUSP4 与多西他赛联合司美替尼的临床反应相关。DUSP4 耗竭诱导 MEKi 耐药,提示 DUSP4 不仅是一种生物标志物,也是 MEKi 敏感性的介质。 临床试验注册: DOC-MEK (EudraCT no: 2009-018153-23)。

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