PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma
PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma
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DOI：
10.3390/cancers11060751
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发表时间：
2019-06-01
期刊：
影响因子：
5.2
通讯作者：
Nemati, Fariba
中科院分区：
文献类型：
--
作者：
De Koning, Leanne;Decaudin, Didier;Nemati, Fariba
葡萄膜黑色素瘤（UM）在转移期仍然没有有效的治疗，这与BAP-1 （BRCA1相关蛋白）突变有关。然而，没有关于UM DNA修复能力的数据。在这里，我们使用UM患者来源的异种移植物（PDXs）来研究PARP抑制剂奥拉帕尼单独或联合的治疗活性。首先，我们发现PARP蛋白的表达和活性在pdx和相应患者肿瘤之间是相似的。PDX模型的体内实验表明，奥拉帕尼单用并不有效，但能显著提高达卡巴嗪的疗效。最后，利用逆相蛋白阵列和免疫组织化学，我们确定了参与DNA修复和细胞凋亡的蛋白质，作为预测奥拉帕尼和达卡巴嗪联合治疗反应的潜在生物标志物。我们还观察到，在达卡巴嗪+奥拉帕尼治疗后，磷酸化的YAP和TAZ蛋白高度增加。我们的研究结果表明，PARP抑制与烷基化剂达卡巴嗪联合可能是UM治疗的临床兴趣。我们还观察到达卡巴嗪对Hippo通路的有趣作用，证实了该通路在UM中的重要性。
Uveal melanoma (UM) remains without effective therapy at the metastatic stage, which is associated with BAP-1 (BRCA1 associated protein) mutations. However, no data on DNA repair capacities in UM are available. Here, we use UM patient-derived xenografts (PDXs) to study the therapeutic activity of the PARP inhibitor olaparib, alone or in combination. First, we show that the expression and the activity of PARP proteins is similar between the PDXs and the corresponding patient's tumors. In vivo experiments in the PDX models showed that olaparib was not efficient alone, but significantly increased the efficacy of dacarbazine. Finally, using reverse phase protein arrays and immunohistochemistry, we identified proteins involved in DNA repair and apoptosis as potential biomarkers predicting response to the combination of olaparib and dacarbazine. We also observed a high increase of phosphorylated YAP and TAZ proteins after dacarbazine + olaparib treatment. Our results suggest that PARP inhibition in combination with the alkylating agent dacarbazine could be of clinical interest for UM treatment. We also observe an interesting effect of dacarbazine on the Hippo pathway, confirming the importance of this pathway in UM.