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

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)。



作者列表:["Abrahamsson H","Jensen BV","Berven LL","Nielsen DL","Šaltytė Benth J","Johansen JS","Larsen FO","Johansen JS","Ree AH"]

METHODS::In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.

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作者列表:["Suvina V","Kokulnathan T","Wang TJ","Balakrishna RG"]

METHODS::Prostate cancer is one of the primary causes of death around the world. As an important drug, flutamide has been used in the clinical diagnosis of prostate cancer. However, the over dosage and improper discharge of flutamide could affect the living organism. Thus, it necessary to develop the sensor for detection of flutamide with highly sensitivity. In this paper, we report the synthesis of lanthanum cobaltite decorated halloysite nanotube (LCO/HNT) nanocomposite prepared by a facile method and evaluated for selective reduction of flutamide. The as-prepared LCO/HNT nanocomposite shows the best catalytic performance towards detection of flutamide, when compared to other bare and modified electrodes. The good electrochemical performance of the LCO/HNT nanocomposite modified electrode is ascribed to abundant active sites, large specific surface area and their synergetic effects. Furthermore, the LCO/HNT modified electrode exhibits low detection limit (0.002 μM), wide working range (0.009-145 μM) and excellent selectivity with remarkable stability. Meaningfully, the developed electrochemical sensor was applied in real environmental samples with an acceptable recovery range.

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来源期刊:Cancer letters
作者列表:["Zhou Z","Zhou Q","Wu X","Xu S","Hu X","Tao X","Li B","Peng J","Li D","Shen L","Cao Y","Yang L"]

METHODS::Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in lung cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.

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