Chemical Genomics Identifies Small-Molecule MCL1 Repressors and BCL-xL as a Predictor of MCL1 Dependency

Guo Wei; Adam A. Margolin; Leila Haery; Emily Brown; Lisa Cucolo; Bina Julian; Shyemaa Shehata; Andrew L. Kung; Rameen Beroukhim; Todd R. Golub

doi:10.1016/j.ccr.2012.02.028

Chemical Genomics Identifies Small-Molecule MCL1 Repressors and BCL-xL as a Predictor of MCL1 Dependency

Guo Wei, Adam A. Margolin, Leila Haery, Emily Brown, Lisa Cucolo, Bina Julian, Shyemaa Shehata, Andrew L. Kung, Rameen Beroukhim, Todd R. Golub

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

148 Scopus citations

Abstract

MCL1, which encodes the antiapoptotic protein MCL1, is among the most frequently amplified genes in human cancer. A chemical genomic screen identified compounds, including anthracyclines, that decreased MCL1 expression. Genomic profiling indicated that these compounds were global transcriptional repressors that preferentially affect MCL1 due to its short mRNA half-life. Transcriptional repressors and MCL1 shRNAs induced apoptosis in the same cancer cell lines and could be rescued by physiological levels of ectopic MCL1 expression. Repression of MCL1 released the proapoptotic protein BAK from MCL1, and Bak deficiency conferred resistance to transcriptional repressors. A computational model, validated in vivo, indicated that high BCL-xL expression confers resistance to MCL1 repression, thereby identifying a patient-selection strategy for the clinical development of MCL1 inhibitors.

Original language	English (US)
Pages (from-to)	547-562
Number of pages	16
Journal	Cancer Cell
Volume	21
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2012.02.028
State	Published - Apr 17 2012
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccr.2012.02.028

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title = "Chemical Genomics Identifies Small-Molecule MCL1 Repressors and BCL-xL as a Predictor of MCL1 Dependency",

abstract = "MCL1, which encodes the antiapoptotic protein MCL1, is among the most frequently amplified genes in human cancer. A chemical genomic screen identified compounds, including anthracyclines, that decreased MCL1 expression. Genomic profiling indicated that these compounds were global transcriptional repressors that preferentially affect MCL1 due to its short mRNA half-life. Transcriptional repressors and MCL1 shRNAs induced apoptosis in the same cancer cell lines and could be rescued by physiological levels of ectopic MCL1 expression. Repression of MCL1 released the proapoptotic protein BAK from MCL1, and Bak deficiency conferred resistance to transcriptional repressors. A computational model, validated in vivo, indicated that high BCL-xL expression confers resistance to MCL1 repression, thereby identifying a patient-selection strategy for the clinical development of MCL1 inhibitors.",

author = "Guo Wei and Margolin, {Adam A.} and Leila Haery and Emily Brown and Lisa Cucolo and Bina Julian and Shyemaa Shehata and Kung, {Andrew L.} and Rameen Beroukhim and Golub, {Todd R.}",

note = "Funding Information: This work was supported by NIH grant nos. P01 CA068484 and 5U54CA112962 (to T.R.G.). G.W. was supported by a postdoctoral fellowship from The Damon Runyon Cancer Research Foundation. R.B. was supported by a grant from the Novartis Institutes of Biomedical Research. The authors thank the Broad Institute Chemical Biology Platform for assistance in small-molecule screening; the Broad Institute Genetic Analysis Platform for Affymetrix microarray profiling; the Broad-Novartis Cancer Cell Line Encyclopedia Project for data sharing; Joshua Gould for assistance in data analysis; Jinyan Du, Xiaodong Lu, and Emily Gray for technical assistance; and Leslie Gaffney and Lauren Solomon for editorial assistance. ",

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doi = "10.1016/j.ccr.2012.02.028",

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AU - Wei, Guo

AU - Margolin, Adam A.

AU - Haery, Leila

AU - Brown, Emily

AU - Cucolo, Lisa

AU - Julian, Bina

AU - Shehata, Shyemaa

AU - Kung, Andrew L.

AU - Beroukhim, Rameen

AU - Golub, Todd R.

N1 - Funding Information: This work was supported by NIH grant nos. P01 CA068484 and 5U54CA112962 (to T.R.G.). G.W. was supported by a postdoctoral fellowship from The Damon Runyon Cancer Research Foundation. R.B. was supported by a grant from the Novartis Institutes of Biomedical Research. The authors thank the Broad Institute Chemical Biology Platform for assistance in small-molecule screening; the Broad Institute Genetic Analysis Platform for Affymetrix microarray profiling; the Broad-Novartis Cancer Cell Line Encyclopedia Project for data sharing; Joshua Gould for assistance in data analysis; Jinyan Du, Xiaodong Lu, and Emily Gray for technical assistance; and Leslie Gaffney and Lauren Solomon for editorial assistance.

PY - 2012/4/17

Y1 - 2012/4/17

N2 - MCL1, which encodes the antiapoptotic protein MCL1, is among the most frequently amplified genes in human cancer. A chemical genomic screen identified compounds, including anthracyclines, that decreased MCL1 expression. Genomic profiling indicated that these compounds were global transcriptional repressors that preferentially affect MCL1 due to its short mRNA half-life. Transcriptional repressors and MCL1 shRNAs induced apoptosis in the same cancer cell lines and could be rescued by physiological levels of ectopic MCL1 expression. Repression of MCL1 released the proapoptotic protein BAK from MCL1, and Bak deficiency conferred resistance to transcriptional repressors. A computational model, validated in vivo, indicated that high BCL-xL expression confers resistance to MCL1 repression, thereby identifying a patient-selection strategy for the clinical development of MCL1 inhibitors.

AB - MCL1, which encodes the antiapoptotic protein MCL1, is among the most frequently amplified genes in human cancer. A chemical genomic screen identified compounds, including anthracyclines, that decreased MCL1 expression. Genomic profiling indicated that these compounds were global transcriptional repressors that preferentially affect MCL1 due to its short mRNA half-life. Transcriptional repressors and MCL1 shRNAs induced apoptosis in the same cancer cell lines and could be rescued by physiological levels of ectopic MCL1 expression. Repression of MCL1 released the proapoptotic protein BAK from MCL1, and Bak deficiency conferred resistance to transcriptional repressors. A computational model, validated in vivo, indicated that high BCL-xL expression confers resistance to MCL1 repression, thereby identifying a patient-selection strategy for the clinical development of MCL1 inhibitors.

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Chemical Genomics Identifies Small-Molecule MCL1 Repressors and BCL-xL as a Predictor of MCL1 Dependency

Abstract

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