1. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance.
- Author
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Wei G, Twomey D, Lamb J, Schlis K, Agarwal J, Stam RW, Opferman JT, Sallan SE, den Boer ML, Pieters R, Golub TR, and Armstrong SA
- Subjects
- Animals, Cell Line, Tumor, Cell Survival drug effects, Databases, Genetic, Dexamethasone pharmacology, Dose-Response Relationship, Drug, Drug Combinations, Drug Resistance, Neoplasm, Green Fluorescent Proteins metabolism, Humans, Mice, Myeloid Cell Leukemia Sequence 1 Protein, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Sirolimus pharmacology, Gene Expression drug effects, Genomics, Glucocorticoids pharmacology, Neoplasm Proteins metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Sirolimus metabolism
- Abstract
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.
- Published
- 2006
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