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Cancer Cell DOI:10.1016/j.ccr.2012.02.028

Chemical genomics identifies small-molecule MCL1 repressors and BCL-xL as a predictor of MCL1 dependency.

Publication TypeJournal Article
Year of Publication2012
AuthorsWei, G, Margolin, AA, Haery, L, Brown, E, Cucolo, L, Julian, B, Shehata, S, Kung, AL, Beroukhim, R, Golub, TR
JournalCancer Cell
Date Published2012 Apr 17
KeywordsAnimals, Apoptosis, bcl-2 Homologous Antagonist-Killer Protein, bcl-X Protein, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Gene Silencing, Genomics, Humans, Mice, Models, Genetic, Myeloid Cell Leukemia Sequence 1 Protein, Proto-Oncogene Proteins c-bcl-2, RNA, Small Interfering, Small Molecule Libraries

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.


Alternate JournalCancer Cell
PubMed ID22516262
PubMed Central IDPMC3685408
Grant ListP01 CA068484 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
5U54CA112962 / CA / NCI NIH HHS / United States
/ / Intramural NIH HHS / United States