Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance.
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.
Wei
Guo
G
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Twomey
David
D
Lamb
Justin
J
Schlis
Krysta
K
Agarwal
Jyoti
J
Stam
Ronald W
RW
Opferman
Joseph T
JT
Sallan
Stephen E
SE
den Boer
Monique L
ML
Pieters
Rob
R
Golub
Todd R
TR
Armstrong
Scott A
SA
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
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