Unknown,Transcriptomics,Genomics,Proteomics

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Response and resistance to BET bromodomain inhibitors in triple negative breast cancer [RNA-Seq]

ABSTRACT: Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. RNA-Seq in parental and JQ1 resistant triple negative breast cancer (TNBC) in response to DMSO or JQ1 treatment over time

ORGANISM(S): Homo sapiens

SUBMITTER: Kornelia Polyak

PROVIDER: E-GEOD-63582 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.

Shu Shaokun S Lin Charles Y CY He Housheng Hansen HH Witwicki Robert M RM Tabassum Doris P DP Roberts Justin M JM Janiszewska Michalina M Huh Sung Jin SJ Liang Yi Y Ryan Jeremy J Doherty Ernest E Mohammed Hisham H Guo Hao H Stover Daniel G DG Ekram Muhammad B MB Brown Jonathan J D'Santos Clive C Krop Ian E IE Dillon Deborah D McKeown Michael M Ott Christopher C Qi Jun J Ni Min M Rao Prakash K PK Duarte Melissa M Wu Shwu-Yuan SY Chiang Cheng-Ming CM Anders Lars L Young Richard A RA Winer Eric E Letai Antony A Barry William T WT Carroll Jason S JS Long Henry H Brown Myles M Liu X Shirley XS Meyer Clifford A CA Bradner James E JE Polyak Kornelia K

Nature 20160106 7586

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to ...[more]

PMID: 26735014

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Project description:Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically-defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anti-cancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, demonstrate a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma. JQ1 is a novel thieno-triazolo-1,4-diazepine, which displaces BET bromodomains from chromatin by competitively binding to the acetyl lysine recognition pocket. BE(2)-C and Kelly cells were treated in triplicate with 1 ÂµM JQ1 or DMSO for 24 hours. RNA was extracted and a decrease in MYCN transcript was confirmed by real time RT-PCR as described above. The samples were profiled using the Affymetrix PrimeView Human Gene Expression Array (Affymetrix) at Beth Israel Deaconess Medical Center (Boston, MA, USA).

Dataset Information

Response and resistance to BET bromodomain inhibitors in triple negative breast cancer [RNA-Seq]

Publications

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.

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