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

doi:10.1016/j.ccr.2006.09.006

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

Research output: Contribution to journal › Article › peer-review

442 Citations (Scopus)

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 language	English
Pages (from-to)	331-42
Number of pages	12
Journal	Cancer cell
Volume	10
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2006.09.006
Publication status	Published - Oct 2006
Externally published	Yes

Keywords

Animals
Cell Line, Tumor
Cell Survival/drug effects
Databases, Genetic
Dexamethasone/pharmacology
Dose-Response Relationship, Drug
Drug Combinations
Drug Resistance, Neoplasm
Gene Expression/drug effects
Genomics
Glucocorticoids/pharmacology
Green Fluorescent Proteins/metabolism
Humans
Mice
Myeloid Cell Leukemia Sequence 1 Protein
Neoplasm Proteins/metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
Proto-Oncogene Proteins c-bcl-2/metabolism
Sirolimus/metabolism

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10.1016/j.ccr.2006.09.006

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@article{88724741d8084d0d8a7946788b9d382e,

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.",

keywords = "Animals, Cell Line, Tumor, Cell Survival/drug effects, Databases, Genetic, Dexamethasone/pharmacology, Dose-Response Relationship, Drug, Drug Combinations, Drug Resistance, Neoplasm, Gene Expression/drug effects, Genomics, Glucocorticoids/pharmacology, Green Fluorescent Proteins/metabolism, Humans, Mice, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins/metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy, Proto-Oncogene Proteins c-bcl-2/metabolism, Sirolimus/metabolism",

author = "Guo Wei and David Twomey and Justin Lamb and Krysta Schlis and Jyoti Agarwal and Stam, {Ronald W} and Opferman, {Joseph T} and Sallan, {Stephen E} and {den Boer}, {Monique L} and Rob Pieters and Golub, {Todd R} and Armstrong, {Scott A}",

note = "Funding Information: We thank Mari Nishino, Jinyan Du, and Paula Bernasconi for assistance. We thank Eric Smith and Elise Porter for help with artwork, editing, and administrative assistance. We also thank the German COALL (coordinated by G. Janka-Schaub, Children's Hospital Eppendorf, Hamburg, Germany) study groups for providing samples. This work was supported by The Leukemia Lymphoma Society (S.A.A.), the Damon Runyon Cancer Research Foundation (S.A.A. and G.W.), and the National Cancer Institute (NCI grants K08 CA92551 and PO1 CA068484). ",

year = "2006",

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doi = "10.1016/j.ccr.2006.09.006",

language = "English",

volume = "10",

pages = "331--42",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

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AU - Wei, Guo

AU - Twomey, David

AU - Lamb, Justin

AU - Schlis, Krysta

AU - Agarwal, Jyoti

AU - Stam, Ronald W

AU - Opferman, Joseph T

AU - Sallan, Stephen E

AU - den Boer, Monique L

AU - Pieters, Rob

AU - Golub, Todd R

AU - Armstrong, Scott A

N1 - Funding Information: We thank Mari Nishino, Jinyan Du, and Paula Bernasconi for assistance. We thank Eric Smith and Elise Porter for help with artwork, editing, and administrative assistance. We also thank the German COALL (coordinated by G. Janka-Schaub, Children's Hospital Eppendorf, Hamburg, Germany) study groups for providing samples. This work was supported by The Leukemia Lymphoma Society (S.A.A.), the Damon Runyon Cancer Research Foundation (S.A.A. and G.W.), and the National Cancer Institute (NCI grants K08 CA92551 and PO1 CA068484).

PY - 2006/10

Y1 - 2006/10

N2 - 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.

AB - 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.

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KW - Genomics

KW - Glucocorticoids/pharmacology

KW - Green Fluorescent Proteins/metabolism

KW - Humans

KW - Mice

KW - Myeloid Cell Leukemia Sequence 1 Protein

KW - Neoplasm Proteins/metabolism

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy

KW - Proto-Oncogene Proteins c-bcl-2/metabolism

KW - Sirolimus/metabolism

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DO - 10.1016/j.ccr.2006.09.006

M3 - Article

C2 - 17010674

SN - 1535-6108

VL - 10

SP - 331

EP - 342

JO - Cancer cell

JF - Cancer cell

IS - 4

ER -

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

Abstract

Keywords

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