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RAPID resistance to BET inhibitors is mediated by FGFR1 in glioblastoma
Anna M Jermakowicz1, Alison M Kurimchak2, Katherine J Johnson2
1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20007, USA.
Abstract:
Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that intrinsic resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Additionally, small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.
Insights
Glioblastoma (GBM) resistance to Bromodomain and extra-terminal domain (BET) inhibitors emerges rapidly, involving fibroblast growth factor receptor 1 (FGFR1). Co-targeting BET and FGFR1 shows promise for overcoming resistance and improving GBM treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets for glioblastoma (GBM).
- Existing BET inhibitors have shown limited efficacy in clinical trials for GBM patients.
- Mechanisms and timing of resistance to BET inhibitors in GBM remain largely unknown.
Purpose of the Study:
- To elucidate the temporal order of resistance mechanisms to BET inhibitors in GBM.
- To identify specific molecular players involved in rapid resistance development.
- To evaluate the therapeutic potential of combined BET and fibroblast growth factor receptor 1 (FGFR1) inhibition in GBM.
Main Methods:
- Quantitative proteomics using multiplex-inhibitor bead mass spectrometry to analyze resistance mechanisms.
- In vitro and in vivo studies assessing the efficacy of single and combined BET and FGFR1 inhibition.
- FGFR1 knockdown experiments to evaluate synergistic effects with BET inhibitors.
Main Results:
- Intrinsic resistance to BET inhibitors in GBM occurs rapidly, within hours.
- Fibroblast growth factor receptor 1 (FGFR1) is identified as a key mediator of this rapid resistance.
- Simultaneous inhibition of BET proteins and FGFR1 demonstrates synergistic effects in reducing GBM tumor growth and cell proliferation.
- FGFR1 knockdown also synergizes with BET inhibitors to reduce GBM cell proliferation.
Conclusions:
- Rapid resistance mechanisms to BET inhibitors in GBM involve FGFR1.
- Co-targeting BET and FGFR1 presents a promising strategy to overcome resistance and enhance therapeutic response in GBM.
- Combined inhibition may dampen resistance pathways, leading to improved clinical outcomes for GBM patients.
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