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Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer
Shaokun Shu1,2, Charles Y Lin1,2, Housheng Hansen He1,2,3,4,5
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Abstract:
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 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.
Insights
Triple-negative breast cancer (TNBC) shows promise with BET bromodomain inhibitors, offering a potential new therapy. Research reveals mechanisms of resistance, suggesting combination strategies for improved treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies.
- BET bromodomain inhibitors have shown efficacy in other cancers but remain unevaluated in TNBC.
- These inhibitors target oncogenic transcriptional programs by displacing BET proteins from chromatin.
Purpose of the Study:
- To evaluate the efficacy of BET bromodomain inhibitors in TNBC.
- To investigate mechanisms of acquired resistance to BET inhibition in TNBC.
- To identify potential combination strategies to overcome resistance.
Main Methods:
- In vitro and in vivo studies of TNBC sensitivity to BET inhibition.
- Analysis of paired cell lines selected for acquired resistance.
- Proteomic studies to identify molecular alterations in resistant cells.
- Assessing BRD4 dependency and post-translational modifications.
Main Results:
- TNBCs exhibit preferential sensitivity to BET bromodomain inhibition.
- Acquired resistance does not involve gatekeeper mutations, new drivers, or drug pump activation.
- Resistant cells remain dependent on wild-type BRD4 in a bromodomain-independent manner.
- MED1 association and BRD4 hyper-phosphorylation due to decreased PP2A activity characterize resistant cells.
Conclusions:
- BET bromodomain inhibition is a promising therapeutic strategy for TNBC.
- Understanding resistance mechanisms involving BRD4 and PP2A is crucial.
- Mechanism-based combination strategies can potentially overcome clinical drug resistance in TNBC.
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