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Targeting Fibroblast Growth Factor Receptor (FGFR) with BGJ398 in a Gastric Cancer Model
Katharina Schmidt1, Christian Moser1, Claus Hellerbrand2
1Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
Aim:
To assess the efficacy of targeting fibroblast growth factor receptor (FGFR) with the pan-FGFR inhibitor BGJ398 in a gastric cancer (GC) model.
Materials And Methods:
Expression of FGFRs was determined in GC cell lines (KKLS, MKN-45, TMK-1). Impact of the FGFR inhibitor BGJ398 on growth, motility, signaling, expression of transcription factors and secretion of vascular endothelial growth factor-A (VEGFA) was determined in vitro. Results were validated in subcutaneous tumor models.
Results:
In vitro, FGFR inhibition was most effective in KKLS cells (high FGFR1, FGFR2IIIc, no FGFR2IIIb expression) with inhibition of growth, motility, signaling, c-MYC expression and VEGFA secretion. BGJ398 showed some activity in MKN-45 cells (intermediate FGFR1, high FGFR2IIIb, low FGFR2IIIc expression), while TMK-1 cells (low FGFR1, no FGFR2IIIb and FGFR2IIIc expression) did not respond. Results were confirmed in vivo with strongest efficacy on growth in KKLS tumors and only minor impairment of TMK-1 lesions.
Conclusion:
Efficacy of FGFR inhibition is dependent on FGFR1 and FGFR2IIIc expression in GC models.
Insights
Targeting fibroblast growth factor receptor (FGFR) with BGJ398 effectively inhibited gastric cancer cell growth, particularly in models with high FGFR1 and FGFR2IIIc expression. Efficacy varied based on specific FGFR profiles.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Gastric cancer (GC) remains a significant health challenge with limited targeted therapy options.
- Fibroblast Growth Factor Receptors (FGFRs) are implicated in various cancers, including GC, making them potential therapeutic targets.
- Understanding FGFR expression patterns is crucial for developing effective targeted treatments.
Purpose of the Study:
- To evaluate the therapeutic potential of BGJ398, a pan-FGFR inhibitor, against gastric cancer.
- To correlate FGFR expression levels with response to FGFR inhibition in GC models.
- To investigate the impact of BGJ398 on GC cell behavior and signaling pathways.
Main Methods:
- Assessed FGFR expression (FGFR1, FGFR2IIIb, FGFR2IIIc) in distinct GC cell lines (KKLS, MKN-45, TMK-1).
- Determined the in vitro effects of BGJ398 on GC cell growth, motility, signaling pathways, transcription factors (e.g., c-MYC), and VEGFA secretion.
- Validated the in vitro findings in subcutaneous GC tumor xenograft models.
Main Results:
- FGFR inhibition by BGJ398 demonstrated significant efficacy in KKLS cells (high FGFR1/FGFR2IIIc) by suppressing growth, motility, signaling, c-MYC, and VEGFA.
- MKN-45 cells (intermediate FGFR1, high FGFR2IIIb) showed partial response to BGJ398.
- TMK-1 cells (low FGFR1, lacking FGFR2IIIb/IIIc) were unresponsive to BGJ398 treatment, both in vitro and in vivo.
Conclusions:
- The efficacy of FGFR inhibition in gastric cancer models is strongly dependent on the expression of specific FGFR isoforms, namely FGFR1 and FGFR2IIIc.
- BGJ398 shows promise as a targeted therapy for GC subtypes characterized by high FGFR1 and FGFR2IIIc expression.
- FGFR expression profiling is essential for patient selection in FGFR-targeted therapies for gastric cancer.
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