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The apoptotic network and expression of BH3-containing proteins predict phenotypic response to BET bromodomain inhibitors

ABSTRACT: Small molecule inhibitors of the bromodomain and extraterminal (BET) family of proteins are in clinical trials for a variety of cancers, but patient selection strategies are limited. This is due in part to the heterogeneity of response following BET inhibition (BETi), which includes differentiation, senescence, and cell death in subsets of cancer cell lines. To elucidate the dominant features defining response to BETi, we carried out phenotypic and gene expression analysis of both treatment naïve cell lines and engineered tolerant lines. We found that both de novo and acquired tolerance to BET inhibition are driven by the robustness of the apoptotic response and that genetic or pharmacological manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further identify that ordered expression of the apoptotic genes BCL2, BCL2L1, and BAD significantly predicts response to BETi. Our findings highlight the role of the apoptotic network in response to BETi, providing a molecular basis for patient stratification and combination therapies. Gene expression profiling of A375 melanoma cells or NOMO-1 AML cells treated with DMSO or the BET inhibitor, CPI203. Also, gene expression profiling of the respective derived BETi-tolerant cells treated with DMSO or CPI203.

ORGANISM(S): Homo sapiens  

SUBMITTER: Richard C Centore  Jennifer A Mertz   Arnaud Amzallag   Patricia Greninger   Barbara M Bryant   Charlie Hatton   Cyril H Benes   Kerry Spillane   Robert J Sims   Nicole E Follmer   Andrew R Conery    

PROVIDER: E-GEOD-69383 | ArrayExpress | 2016-01-07



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