Wei G, Margolin AA, Haery L, Brown E, Cucolo L, Julian B, Shehata S, Kung AL, Beroukhim R, Golub TR. Chemical genomics identifies small-molecule MCL1 repressors and BCL-xL as a predictor of MCL1 dependency. Cancer Cell. 2012;21:547–62.
NOTES
Wei, GuoMargolin, Adam AHaery, LeilaBrown, EmilyCucolo, LisaJulian, BinaShehata, ShyemaaKung, Andrew LBeroukhim, RameenGolub, Todd RengP01 CA068484/CA/NCI NIH HHS/U54 CA112962/CA/NCI NIH HHS/5U54CA112962/CA/NCI NIH HHS/Intramural NIH HHS/Research Support, N.I.H., IntramuralResearch Support, Non-U.S. Gov'tCancer Cell. 2012 Apr 17;21(4):547-62. doi: 10.1016/j.ccr.2012.02.028.
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.
Last updated on 02/17/2021