Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL-1 and glucocorticoid resistance in leukemia

CancerCell October 2006. 10.1016/j.ccr.2006.09.006 . Published: 2006.09.30

Guo Wei, David Twomey, Justin Lamb, Krysta Schlis, Jyoti Agarwal, Ronald Stam, Joseph T. Opferman, Stephen E. Sallan, Monique L. den Boer, Rob Pieters, Todd R. Golub, Scott A. Armstrong.

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Abstract

Drug resistance remains a major obstacle to successful cancer treatment. Here we use a novel approach to identify rapamycin as a glucocorticoid resistance reversal agent. A database of drugassociated 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 the mTOR inhibitor rapamycin profile matched the signature of GCsensitivity. We thus tested the hypothesis that rapamycin would induce GC sensitivity in GC resistant lymphoid cells, and found that it sensitized cells to glucocorticoid induced apoptosis via modulation of antiapoptotic MCL1. These data indicate that MCL1 is an important regulator of GC-induced apoptosis, and that rapamycin is a potential therapeutic for GC-resistant ALL. Furthermore this approach represents a novel strategy for identification of promising combination therapies for cancer.

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Supplemental Data

Description Link/Filename
ALL Patient Samples Children_NE.gct
Rapamycin treated CEM-C1 cell line(24 hour). Rap24hour_Control.gct
Rapamycin treated CEM-C1 cell line(3 hour). Rap3hour_control.gct
Resistant/Sensitive Signatures. http://www.broadinstitute.org/mpr/publications/projects/Leukemia/
Resistant Markers p-value <=0.0005 Res_p0005.gct
Sensitive Markers p-value <=0.0005 Sens_p0005.gct
Resistant Markers p-value <=0.001 Res_p001.gct
Sensitive Markers p-value <=0.001 Sens_p001.gct
Zip of all CEL files armstrong.zip