Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance

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• 作者：Guo Wei ; David Twomey ; Justin Lamb ; Krysta Schlis ; Jyoti Agarwal ; Ronald W. Stam ; Joseph T. Opferman ; Stephen E. Sallan ; Monique L. den Boer ; Rob Pieters ; Todd R. Golub ; Scott A. Armstrong
• 关键词：CELLCYCLE
• 刊名：Cancer Cell
• 出版年：2006
• 出版时间：October 2006
• 年：2006
• 卷：10
• 期：4
• 页码：331-342
• 全文大小：738 K

文摘

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.