Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance
Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance
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DOI：
10.1016/j.ccr.2006.09.006
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发表时间：
2006-10-01
期刊：
影响因子：
50.3
通讯作者：
Armstrong, Scott A.
中科院分区：
文献类型：
--
作者：
Wei, Guo;Twomey, David;Armstrong, Scott A.
耐药性仍然是成功治疗癌症的主要障碍。在药物相关基因表达谱数据库中筛选了与急性淋巴细胞白血病 (ALL) 细胞中糖皮质激素 (GC) 敏感性/耐药性的基因表达特征重叠的分子。筛选表明 mTOR 抑制剂雷帕霉素谱与 GC 敏感性特征相匹配。我们测试了雷帕霉素会诱导淋巴恶性肿瘤细胞对 GC 敏感性的假设，发现它通过调节抗凋亡 MCL1 来对 GC 诱导的细胞凋亡敏感。这些数据表明，MCL1 是 GC 诱导细胞凋亡的重要调节因子，雷帕霉素和糖皮质激素的组合在淋巴恶性肿瘤中具有潜在用途。此外，这种方法代表了一种识别有前途的癌症联合疗法的策略。
Drug resistance remains a major obstacle to successful cancer treatment. A database of drug-associated gene expression profiles was screened for molecules whose profile overlapped with a gene expression signature of glucocorticoid (GC) sensitivity/resistance in acute lymphoblastic leukemia (ALL) cells. The screen indicated that the mTOR inhibitor rapamycin profile matched the signature of GC sensitivity. We tested the hypothesis that rapamycin would induce GC sensitivity in lymphoid malignancy cells and found that it sensitized to GC-induced apoptosis via modulation of antiapoptotic MCL1. These data indicate that MCL1 is an important regulator of GC-induced apoptosis and that the combination of rapamycin and glucocorticoids has potential utility in lymphoid malignancies. Furthermore, this approach represents a strategy for identification of promising combination therapies for cancer.