Systems modeling accurately predicts responses to genotoxic agents and their synergism with BCL-2 inhibitors in triple negative breast cancer cells.
Systems modeling accurately predicts responses to genotoxic agents and their synergism with BCL-2 inhibitors in triple negative breast cancer cells.
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DOI：
10.1038/s41419-017-0039-y
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发表时间：
2018-01-19
影响因子：
9
通讯作者：
Prehn JHM
中科院分区：
文献类型：
--
作者：
Lucantoni F;Lindner AU;O'Donovan N;Düssmann H;Prehn JHM
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌，占该疾病的15-20%，目前用遗传毒性化疗治疗。BCL 2（B细胞淋巴瘤2）蛋白家族控制线粒体外膜透化（MOMP）过程，这是响应遗传毒性剂激活线粒体凋亡途径所必需的。我们先前开发了BCL 2蛋白相互作用的确定性系统模型DR_MOMP，其计算细胞经历线粒体凋亡的敏感性。在这里，我们确定DR_MOMP是否预测TNBC细胞对遗传毒性剂的反应以及BCL 2抑制剂对抗性细胞的再致敏。使用BAX、巴克、BCL 2、BCL（X）L和MCL 1的绝对蛋白水平作为DR_MOMP的输入，我们发现模型预测与一组TNBC细胞对24和48小时顺铂（R2分别= 0.96和0.95）和紫杉醇治疗（R2分别= 0.94和0.95）的反应之间存在强相关性。这优于单蛋白相关性（表现最佳的BCL（X）L，顺铂和紫杉醇治疗的R2分别为0.69和0.50）和BCL 2蛋白比率（顺铂的R2为0.50，紫杉醇的R2为0.49）。接下来，我们使用BCL 2选择性拮抗剂Venetoclax /ABT 199、BCL（X）L选择性拮抗剂WEHI-539或MCL 1选择性拮抗剂A-1210477与顺铂组合进行协同作用研究。DR_MOMP的计算机模拟预测显示，BCL（X）L、BCL 2或MCL 1抑制剂与顺铂联合治疗的疗效存在显著差异，这些结果在细胞系中得到了成功验证。我们的研究结果提供了DR_MOMP预测TNBC细胞对遗传毒性治疗的反应的证据，并且可以帮助选择用于耐药细胞的组合治疗的最佳BCL 2蛋白拮抗剂。
Triple negative breast cancer (TNBC) is an aggressive form of breast cancer which accounts for 15–20% of this disease and is currently treated with genotoxic chemotherapy. The BCL2 (B-cell lymphoma 2) family of proteins controls the process of mitochondrial outer membrane permeabilization (MOMP), which is required for the activation of the mitochondrial apoptosis pathway in response to genotoxic agents. We previously developed a deterministic systems model of BCL2 protein interactions, DR_MOMP that calculates the sensitivity of cells to undergo mitochondrial apoptosis. Here we determined whether DR_MOMP predicts responses of TNBC cells to genotoxic agents and the re-sensitization of resistant cells by BCL2 inhibitors. Using absolute protein levels of BAX, BAK, BCL2, BCL(X)L and MCL1 as input for DR_MOMP, we found a strong correlation between model predictions and responses of a panel of TNBC cells to 24 and 48 h cisplatin (R2 = 0.96 and 0.95, respectively) and paclitaxel treatments (R2 = 0.94 and 0.95, respectively). This outperformed single protein correlations (best performer BCL(X)L with R2 of 0.69 and 0.50 for cisplatin and paclitaxel treatments, respectively) and BCL2 proteins ratio (R2 of 0.50 for cisplatin and 0.49 for paclitaxel). Next we performed synergy studies using the BCL2 selective antagonist Venetoclax /ABT199, the BCL(X)L selective antagonist WEHI-539, or the MCL1 selective antagonist A-1210477 in combination with cisplatin. In silico predictions by DR_MOMP revealed substantial differences in treatment responses of BCL(X)L, BCL2 or MCL1 inhibitors combinations with cisplatin that were successfully validated in cell lines. Our findings provide evidence that DR_MOMP predicts responses of TNBC cells to genotoxic therapy, and can aid in the choice of the optimal BCL2 protein antagonist for combination treatments of resistant cells.
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
--
作者：
Keitel U;Scheel A;Thomale J;Halpape R;Kaulfuß S;Scheel C;Dobbelstein M
通讯作者：
Dobbelstein M
影响因子：
21.3
作者：
Chen HC;Kanai M;Inoue-Yamauchi A;Tu HC;Huang Y;Ren D;Kim H;Takeda S;Reyna DE;Chan PM;Ganesan YT;Liao CP;Gavathiotis E;Hsieh JJ;Cheng EH
通讯作者：
Cheng EH
影响因子：
12.4
作者：
Goodwin, C. M.;Rossanese, O. W.;Fesik, S. W.
通讯作者：
Fesik, S. W.