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

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

Research output: Contribution to journalArticle

112 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 languageEnglish (US)
Pages (from-to)547-562
Number of pages16
JournalCancer Cell
Volume21
Issue number4
DOIs
Publication statusPublished - Apr 17 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

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