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Targeting ESR1 mutation-induced transcriptional addiction in breast cancer with BET inhibition
Sm N Udden1, Qian Wang1, Sunil Kumar2,3
1Department of Radiation Oncology, University of Texas (UT) Southwestern Medical Center, Dallas, Texas, USA.
Abstract:
Acquired mutations in the ligand-binding domain (LBD) of the gene encoding estrogen receptor α (ESR1) are common mechanisms of endocrine therapy resistance in patients with metastatic ER+ breast cancer. The 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 1,200 Federal Drug Administration-approved (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 WT cells. Thus, BET inhibition has the potential to both prevent and overcome ESR1 mutant-induced endocrine therapy resistance in breast cancer.
Insights
Bromodomain and extraterminal domain (BET) inhibitor OTX015 effectively suppresses estrogen receptor α (ESR1) Y537S mutant breast cancer cell growth. BET inhibition shows potential to prevent and overcome endocrine therapy resistance in metastatic ER+ breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Acquired mutations in estrogen receptor α (ESR1) ligand-binding domain (LBD) drive endocrine therapy resistance in metastatic ER+ breast cancer.
- The ESR1 Y537S mutation is a key driver of resistance to standard breast cancer therapies.
Purpose of the Study:
- To identify novel therapeutic agents targeting ESR1 mutant breast cancer.
- To evaluate the efficacy of OTX015, a BET inhibitor, in overcoming ESR1-mediated endocrine resistance.
Main Methods:
- High-throughput screening of nearly 1,200 FDA-approved drugs.
- In vitro cell growth assays and in vivo xenograft models.
- Combination therapy studies with abemaciclib and fulvestrant.
Main Results:
- OTX015 demonstrated significant suppression of ESR1 mutant cell growth, outperforming fulvestrant in xenograft models.
- Combination of OTX015 and abemaciclib achieved superior tumor regression compared to standard-of-care.
- OTX015 exhibited preferential activity against Y537S mutant cells and inhibited clonal selection.
Conclusions:
- Bromodomain and extraterminal domain (BET) inhibition, specifically with OTX015, is a promising strategy against ESR1 Y537S-driven endocrine resistance.
- OTX015 has the potential to prevent and overcome endocrine therapy resistance in ER+ breast cancer.
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