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

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

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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.

Original languageEnglish (US)
Pages (from-to)331-342
Number of pages12
JournalCancer Cell
Volume10
Issue number4
DOIs
StatePublished - Oct 1 2006

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Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Wei, G., Twomey, D., Lamb, J., Schlis, K., Agarwal, J., Stam, R. W., Opferman, J. T., Sallan, S. E., den Boer, M. L., Pieters, R., Golub, T. R., & Armstrong, S. A. (2006). Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell, 10(4), 331-342. https://doi.org/10.1016/j.ccr.2006.09.006