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FGFR1 Induces Glioblastoma Radioresistance through the PLCγ/Hif1α Pathway
Valérie Gouazé-Andersson1, Caroline Delmas2, Marion Taurand1
1Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037/Université Toulouse III Paul Sabatier, Cancer Research Center of Toulouse (CRCT), Team 11, Toulouse, France.
Abstract:
FGF2 signaling in glioblastoma induces resistance to radiotherapy, so targeting FGF2/FGFR pathways might offer a rational strategy for tumor radiosensitization. To investigate this possibility, we evaluated a specific role for FGFR1 in glioblastoma radioresistance as modeled by U87 and LN18 glioblastomas in mouse xenograft models. Silencing FGFR1 decreased radioresistance in a manner associated with radiation-induced centrosome overduplication and mitotic cell death. Inhibiting PLCγ (PLCG1), a downstream effector signaling molecule for FGFR1, was sufficient to produce similar effects, arguing that PLCγ is an essential mediator of FGFR1-induced radioresistance. FGFR1 silencing also reduced expression of HIF1α, which in addition to its roles in hypoxic responses exerts an independent effect on radioresistance. Finally, FGFR1 silencing delayed the growth of irradiated tumor xenografts, in a manner that was associated with reduced HIF1α levels but not blood vessel alterations. Taken together, our results offer a preclinical proof of concept that FGFR1 targeting can degrade radioresistance in glioblastoma, a widespread problem in this tumor, prompting clinical investigations of the use of FGFR1 inhibitors for radiosensitization. Cancer Res; 76(10); 3036-44. ©2016 AACR.
Insights
Targeting FGFR1 in glioblastoma may overcome radiotherapy resistance. Inhibiting FGFR1 reduces tumor growth and increases cell death after radiation, suggesting FGFR1 inhibitors could enhance cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- Glioblastoma (GBM) exhibits resistance to radiotherapy, partly due to Fibroblast Growth Factor 2 (FGF2) signaling.
- Targeting FGF2/Fibroblast Growth Factor Receptor (FGFR) pathways presents a potential strategy for improving glioblastoma radiosensitization.
Purpose of the Study:
- To investigate the specific role of FGFR1 in glioblastoma radioresistance.
- To evaluate FGFR1 inhibition as a strategy to enhance radiotherapy efficacy in glioblastoma.
Main Methods:
- Utilized U87 and LN18 glioblastoma cell lines in mouse xenograft models.
- Employed FGFR1 silencing and inhibition of its downstream effector, PLCγ (PLCG1).
- Assessed effects on radioresistance, cell death, HIF1α expression, and tumor growth post-irradiation.
Main Results:
- Silencing FGFR1 decreased glioblastoma radioresistance, correlating with increased centrosome overduplication and mitotic cell death.
- Inhibition of PLCγ mimicked FGFR1 silencing effects, indicating PLCγ mediation of FGFR1-induced radioresistance.
- FGFR1 silencing reduced HIF1α expression and delayed irradiated tumor xenograft growth, independent of vascular changes.
Conclusions:
- FGFR1 plays a critical role in mediating glioblastoma radioresistance.
- Targeting FGFR1, potentially via FGFR1 inhibitors, offers a preclinical proof of concept for improving radiotherapy outcomes in glioblastoma.
- Further clinical investigation into FGFR1 inhibitors for glioblastoma radiosensitization is warranted.
