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.
authors.affiliation: Cancer Program, The Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
authors.forename: Guo
authors.initials: G
authors.lastname: Wei
authors.forename: Adam A
authors.initials: AA
authors.lastname: Margolin
authors.forename: Leila
authors.initials: L
authors.lastname: Haery
authors.forename: Emily
authors.initials: E
authors.lastname: Brown
authors.forename: Lisa
authors.initials: L
authors.lastname: Cucolo
authors.forename: Bina
authors.initials: B
authors.lastname: Julian
authors.forename: Shyemaa
authors.initials: S
authors.lastname: Shehata
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D023281:Genomics; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051020:bcl-X Protein / Q000502:physiology*
chemical_list: C494772:BAK1 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein