Identification of JNK1 as a predicting biomarker for ABT‐199 and paclitaxel combination treatment
Identification of JNK1 as a predicting biomarker for ABT‐199 and paclitaxel combination treatment
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DOI：
10.1016/j.bcp.2018.06.019
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发表时间：
2018-09
影响因子：
5.8
通讯作者：
T. Song;Minhang Zhang;Peng Liu;Zhenyu Xue;Yudan Fan;Zhichao Zhang
中科院分区：
文献类型：
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作者：
T. Song;Minhang Zhang;Peng Liu;Zhenyu Xue;Yudan Fan;Zhichao Zhang
在临床前和临床研究中，用ABT-199（维奈托克）靶向Bcl-2显示出对许多癌症的有限的单药活性。联合治疗引起了极大的关注。本研究的主要目的是探讨ABT-199与紫杉醇协同作用的机制。此外，我们分析了生物标志物，以确定最有可能对这种组合产生反应的肿瘤。我们评估了这种组合在一组九种癌细胞系中的作用，包括宫颈癌、肺癌、卵巢癌、淋巴瘤、白血病和乳腺癌。联合指数（CI）分析显示，9个细胞系中有4个细胞系对ABT-199/紫杉醇联合表现出协同反应，这是由于内在凋亡增强。然而，紫杉醇诱导的Bcl-2磷酸化通过阻碍ABT-199释放Bax和Bim而损害协同效应，因为ABT-199不能打击磷酸化的Bcl-2（pBcl-2）。通过JNK水平与CI值的相关性分析，结合癌细胞中JNK蛋白的过表达或沉默，我们确定了基础JNK 1水平作为预测紫杉醇治疗后pBcl-2水平的潜在生物标志物，从而预测协同反应。使用受试者操作特征（ROC）分析确定相对JNK 1表达水平的截止值0.37，以区分协同和非协同反应癌症。将基于大规模临床样本分析获得更准确和有效的JNK 1临界值。
Targeting Bcl-2 with ABT-199 (Venetoclax) shows limited single-agent activity against many cancers in both preclinical and clinical investigations. Combination therapies have attracted great attention. The principal purpose of this study was to investigate the mechanism of synergism between ABT-199 and paclitaxel. Moreover, we analyzed the biomarker to identify tumors which are most likely to respond to this combination. We evaluated the effect of this combination in a panel of nine cancer cell lines including cervical cancer, lung cancer, ovarian cancer, lymphoma, leukemia and breast cancer. Combination index (CI) assay showed that four of nine call lines exhibited synergistic respond to ABT-199/paclitaxel combination due to enhanced intrinsic apoptosis. However, paclitaxel-induced Bcl-2 phosphorylation impaired the synergistic effect by impeding the freeing of Bax and Bim by ABT-199 because ABT-199 cannot hit phosphorylated Bcl-2 (pBcl-2). By means of a correlation analysis of JNK level with CI value in combination with overexpressing or silencing JNK protein in cancer cells, we identified basal JNK1 level as a potential biomarker for predicting the level of pBcl-2 upon paclitaxel treatment, and thus for predicting a synergistic response. A cut-off value of 0.37 for relative JNK1 expression level was determined using receiver operating characteristic (ROC) analysis to distinguish between synergistic and non-synergistic response cancers. A more accurate and valid cut-off value for JNK1 will be gained based on a large-scale clinical samples analysis.