Targeting ESR1 mutation–induced transcriptional addiction in breast cancer with BET inhibition

Abstract

Acquired mutations in the ligand-binding domain (LBD) of the gene encoding Estrogen Receptor alpha (ESR1) are a common mechanism of endocrine therapy resistance in metastatic ER-positive breast cancer patients. ESR1 Y537S mutation, in particular, is associated with development of resistance to most endocrine therapies used to treat breast cancer. Employing a high-throughput screen of nearly 1200 Federal Drug Administration (FDA)-approved drugs, we show that OTX015, a bromodomain and extraterminal domain (BET) inhibitor, is one of the top suppressors of ESR1 mutant cell growth. OTX015 was more efficacious than fulvestrant, a selective ER degrader, in inhibiting ESR1 mutant xenograft growth. When combined with abemaciclib, a CDK4/6 inhibitor, OTX015 induced more potent tumor regression than current standard-of-care treatment of abemaciclib+fulvestrant. OTX015 has preferential activity against Y537S mutant breast cancer cells and blocks their clonal selection in competition studies with wild-type cells. Thus, BET inhibition has the potential to both prevent and overcome ESR1 mutant-induced endocrine therapy resistance in breast cancer.

Towards precision radiation oncology: endocrine therapy response as a biomarker for personalization of breast radiotherapy

“…2a ). Supported by these findings, we hypothesized that BRD4 mediates both ET resistance and RR in BC, and that pharmacologic BET inhibition overcomes RR (in addition to ET resistance as previously shown) 8 , 9 . To test this hypothesis, we conducted cell fractionation assays following IR treatment to evaluate the role of BRD4 in the repair of IR-induced DNA DSBs.…”

“…Targeting pathological transcriptional 6 and DNA repair reprogramming 7 is emerging as a novel approach to overcome treatment resistance in many cancers. The bromodomain and extraterminal domain (BET) family of proteins such as BRD4 are epigenetic regulators that mediate ESR1 mutation-induced “transcriptional addiction” in BC to confer ET resistance 8 . Using a high-throughput screen of nearly 1,200 drugs, we have previously identified OTX015, a BET inhibitor, as one of the top suppressors of ESR1 mutant BC cell and xenograft growth 8 .…”

“…The bromodomain and extraterminal domain (BET) family of proteins such as BRD4 are epigenetic regulators that mediate ESR1 mutation-induced “transcriptional addiction” in BC to confer ET resistance 8 . Using a high-throughput screen of nearly 1,200 drugs, we have previously identified OTX015, a BET inhibitor, as one of the top suppressors of ESR1 mutant BC cell and xenograft growth 8 . Feng and co-workers have previously shown that BET inhibition overcomes tamoxifen resistance in BC by targeting cooperative interactions between BRD4 and WHSC1, a histone H3K36 methytransferase 9 .…”

“…3k, l ). Thus, BRD4 plays a central role in mediating both transcriptional reprogramming that confers ET resistance 8 , 9 , and DNA repair reprogramming that confers RR in ER-positive BC cells.

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“…As a control, we gave six daily doses of OTX015 without radiation (Fig. 3c ), unlike previous studies which administered BET inhibitors daily over several weeks 8 , 9 . Under these conditions, OTX015 did not exert any tumor growth inhibition (Fig.…”