Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy1,2,3. BET bromodomain inhibitors, which have shown efficacy in several models of cancer4,5,6, 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 programs7,8,9. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.
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Gene Expression Omnibus
RNA-seq, ChIP-seq, and Chem-seq data have been deposited in the NCBI GEO database with the accession number GSE63584.
We thank D. Silver and members of the Polyak and Bradner laboratories for their critical reading of this manuscript and useful discussions. We thank G. Brown for help with creating the word cloud figures. This work was supported by the NIH DF/HCC SPORE in Breast Cancer CA168504 (K.P., E.P.W., I.E.K., D.D., W.T.B., and J.E.B.), CA080111 (K.P. and M.B.), and CA103867 (C.M.C.), Susan G. Komen Foundation (S.S.), CPRIT RP110471 and RP140367 (C.M.C), Welch Foundation (C.M.C.), US Department of Defense CDMRP BC122003 (S.X.L.) and CA120184 (C.Y.L.), Princess Margaret Cancer Foundation (H.H.H.), Canada Foundation for Innovation and Ontario Research Fund CFI32372 (H.H.H.), NSERC discovery grant RGPIN-2015-04658 (H.H.H.), and the Harvard Ludwig Center for Cancer Research (J.E.B., M.B. and K.P.).
Extended data figures
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BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic Syndromes
Frontiers in Oncology (2019)