Abstract B16: Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Cancer genome sequencing studies focusing on TNBC failed to identify novel recurrently mutated cancer-driving genes, obviating immediate opportunities for targeted therapeutic development. Here we have identified BET bromodomain inhibitors (BBDIs) as promising novel therapeutic agents in TNBC. Specifically, we have found that TNBC cells are significantly and preferentially growth inhibited by BBDIs (e.g., JQ1) with IC50s in the low nM range compared to luminal breast cancer cells. The growth of established xenografts derived from TNBC cell lines and primary patient samples were also efficiently inhibited by BBDIs treatment. BRD4, a target of BBDIs, is highly expressed in TNBCs compared to luminal cell lines and its downregulation using shRNAs inhibits TNBC cell growth in cell culture and induces tumor regression in vivo. In line with the role of BRD4 in transcription restart after G2/M, BBDI treatment prevented cell cycle re-entry, arrested TNBC cells in early G1, apoptosis, and induced luminal epithelial cell differentiation. Using integrated epigenomic analysis, we have identified the direct transcriptional targets of BBDI in TNBC. BBDI was found to efficiently displace chromatin-bound BRD4 in sensitive TNBC cells. This effect was more pronounced at genomic regions exhibiting elevated Bio-JQ1 binding by Chem-seq, implying strong association betwe...

Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Shu, S., Lin, C., He, H. H., Witwicki, R., Roberts, J., Tabassum, D., Liang, Y., Ekram, M., Doherty, E., Brown, J., Mohammed, H., D'Santos, C., McKeown, M., Ott, C., Qi, J., Ni, M., Rao, P., Duarte, M., Wu, S.-Y., Chiang, C.-M., Young, R., Carroll, J., Lo Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research