title: Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance.
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.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Guo
authors.initials: G
authors.lastname: Wei
authors.forename: David
authors.initials: D
authors.lastname: Twomey
authors.forename: Justin
authors.initials: J
authors.lastname: Lamb
authors.forename: Krysta
authors.initials: K
authors.lastname: Schlis
authors.forename: Jyoti
authors.initials: J
authors.lastname: Agarwal
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Stam
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Opferman
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D030541:Databases, Genetic; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression / Q000187:drug effects*; D023281:Genomics; D005938:Glucocorticoids / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D020123:Sirolimus / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D004338:Drug Combinations; D005938:Glucocorticoids; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D049452:Green Fluorescent Proteins; D003907:Dexamethasone; D020123:Sirolimus