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

被引：169

作者：

Wei, Guo ^{[1
,2
]}

Margolin, Adam A. ^{[1
]}

Haery, Leila ^{[1
]}

Brown, Emily ^{[1
]}

Cucolo, Lisa ^{[1
]}

Julian, Bina ^{[1
]}

Shehata, Shyemaa ^{[3
]}

Kung, Andrew L. ^{[2
]}

Beroukhim, Rameen ^{[1
,3
]}

Golub, Todd R. ^{[1
,2
,4
]}

机构：

[1] Broad Inst Massachusetts Inst Technol & Harvard U, Canc Program, Cambridge, MA 02142 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst, Boston, MA 02115 USA

来源：

CANCER CELL | 2012年 / 21卷 / 04期

关键词：

IMMUNOHISTOCHEMICAL ANALYSIS; REGULATORY NETWORKS; FAMILY PROTEINS; UP-REGULATION; APOPTOSIS; EXPRESSION; RESISTANCE; INHIBITOR; BAX; DOXORUBICIN;

D O I：

10.1016/j.ccr.2012.02.028

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：547 / 562

页数：16

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