Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared with single agents. In addition, a breast cancer patient–derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared with single agents. Mice bearing plasma cell tumors lived an average of 70 days longer on combination treatment compared with single agents. A set of 37 genes cooperatively affected (34 downregulated; 3 upregulated) by the combination responded pharmacodynamically in human myeloma cell lines, xenografts, and a P493 model, and were both enriched in tumors, and correlated with prognostic markers in myeloma patient datasets. Genes downregulated by the combination were overexpressed in several untreated cancers (breast, lung, colon, sarcoma, head and neck, myeloma) compared with normal tissues. The MYC/E2F axis, identified by upstream regulator analyses and validated by immunoblots, was significantly inhibited by the drug combination in several myeloma cell lines. Furthermore, 88% of the 34 genes downregulated have MYC-binding sites in their promoters, and the drug combination cooperatively reduced MYC half-life by 55% and increased degradation. Cells with MYC mutations were refractory to the combination. Thus, integrative approaches to understand drug synergy identified a clinically actionable strategy to inhibit MYC/E2F activity and tumor cell growth in vivo . Mol Cancer Ther; 16(9); 2008–21. ©2017 AACR .

中文翻译：

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联合抑制mTOR / HDAC的合作目标促进MYC降解

癌症治疗通常需要结合分子靶向药物才能有效。已经显示mTORi（雷帕霉素）和HDACi（MS-275 /恩替司他）抑制剂在限制肿瘤生长方面有效，在这里我们定义了这种药物组合的部分协同作用。与单药相比，用这种药物组合治疗的60多种人类癌细胞系具有协同反应（CI <1）。此外，与单药相比，乳腺癌患者衍生的异种移植物和BCL-XL浆细胞瘤小鼠模型均显示出对该组合的增强反应。与单药相比，联合治疗的携带浆细胞瘤的小鼠平均寿命延长了70天。一组37个基因受到合作影响（34个被下调；通过该组合在人骨髓瘤细胞系，异种移植物和P493模型中药效学响应，并且都富含肿瘤，并且与骨髓瘤患者数据集中的预后指标相关。与正常组织相比，该组合下调的基因在几种未经治疗的癌症（乳腺癌，肺癌，结肠癌，肉瘤，头颈癌，骨髓瘤）中过表达。通过上游调节剂分析鉴定并通过免疫印迹验证的MYC / E2F轴在几种骨髓瘤细胞系中被药物组合显着抑制。此外，被下调的34个基因中有88％在其启动子中具有MYC结合位点，并且该药物组合共同使MYC半衰期降低了55％，并增加了降解。具有MYC突变的细胞对该组合物是难治的。因此，理解药物协同作用的综合方法确定了一种临床可行的抑制体内MYC / E2F活性和肿瘤细胞生长的策略。分子癌疗法；16（9）; 2008–21。©2017 AACR。