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Synthetic lethal combination targeting BET uncovered intrinsic susceptibility of TNBC to ferroptosis
Nandini Verma1, Yaron Vinik1, Ashish Saroha1
1Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 20892, Israel.
Abstract:
Identification of targeted therapies for TNBC is an urgent medical need. Using a drug combination screen reliant on synthetic lethal interactions, we identified clinically relevant combination therapies for different TNBC subtypes. Two drug combinations targeting the BET family were further explored. The first, targeting BET and CXCR2, is specific for mesenchymal TNBC and induces apoptosis, whereas the second, targeting BET and the proteasome, is effective for major TNBC subtypes and triggers ferroptosis. Ferroptosis was induced at low drug doses and was associated with increased cellular iron and decreased glutathione levels, concomitant with reduced levels of GPX4 and key glutathione biosynthesis genes. Further functional studies, analysis of clinical datasets and breast cancer specimens revealed a unique vulnerability of TNBC to ferroptosis inducers, enrichment of ferroptosis gene signature, and differential expression of key proteins that increase labile iron and decrease glutathione levels. This study identified potent combination therapies for TNBC and unveiled ferroptosis as a promising therapeutic strategy.
Insights
This study identifies novel drug combinations for triple-negative breast cancer (TNBC) subtypes. Targeting BET proteins with CXCR2 or proteasome inhibitors induces apoptosis or ferroptosis, offering new therapeutic strategies for TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies, representing a critical unmet medical need.
- Synthetic lethality offers a promising approach for identifying effective TNBC combination treatments.
Purpose of the Study:
- To identify clinically relevant combination therapies for distinct TNBC subtypes using a drug combination screen.
- To explore the therapeutic potential of BET family-targeting drug combinations, specifically BET/CXCR2 and BET/proteasome inhibitors.
- To investigate the role of ferroptosis as a therapeutic strategy in TNBC.
Main Methods:
- Conducted a drug combination screen based on synthetic lethal interactions.
- Investigated two BET family-targeting drug combinations: BET/CXCR2 and BET/proteasome inhibitors.
- Performed functional studies, analyzed clinical datasets, and examined breast cancer specimens to validate findings.
Main Results:
- Identified clinically relevant combination therapies for different TNBC subtypes.
- The BET/CXCR2 combination showed specificity for mesenchymal TNBC, inducing apoptosis.
- The BET/proteasome combination proved effective across major TNBC subtypes by triggering ferroptosis, characterized by increased cellular iron and decreased glutathione levels.
- TNBC exhibits a unique vulnerability to ferroptosis inducers, with an enriched ferroptosis gene signature observed.
Conclusions:
- Potent combination therapies for TNBC have been identified, including BET-targeting strategies.
- Ferroptosis is presented as a novel and promising therapeutic strategy for TNBC treatment.
- Understanding TNBC's vulnerability to ferroptosis opens new avenues for drug development.
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