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Published on: September 30, 2019
Fibroblast Growth Factor Receptors as Targets for Radiosensitization in Head and Neck Squamous Cell Carcinomas
Michael M Fisher1, Gopika SenthilKumar1, Rong Hu2
1Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
Purpose:
We examined the capacity of the pan-fibroblast growth factor receptor (FGFR) inhibitor AZD4547 to augment radiation response across a panel of head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts.
Methods And Materials:
FGFR1, FGFR2, and FGFR3 RNA in situ hybridization expression was assessed in a cohort of HNSCC patient samples, cell lines, and patient-derived xenografts (PDXs). In vitro effects of AZD4547 and radiation on cell survival, FGFR signaling, apoptosis, autophagy, cell cycle, and DNA damage repair were evaluated. Reverse phase protein array was used to identify differentially phosphorylated proteins in cells treated with AZD4547. In vivo tumor responses were evaluated in cell lines and PDX models.
Results:
FGFR1, FGFR2, and FGFR3 RNA in situ hybridization were expressed in 41%, 81%, and 89% of 107 oropharynx patient samples. Sensitivity to AZD4547 did not directly correlate with FGFR protein or RNA expression. In sensitive cell lines, AZD4547 inhibited p-MAPK in a time-dependent manner. Significant radiosensitization with AZD4547 was observed in cell lines that were sensitive to AZD4547. The mechanism underlying these effects appears to be multifactorial, involving inhibition of the MTOR pathway and subsequent enhancement of autophagy and activation of apoptotic pathways. Significant tumor growth delay was observed when AZD4547 was combined with radiation compared with radiation or drug alone in an FGFR-expressing HNSCC cell line xenograft and PDX.
Conclusions:
These findings suggest that AZD4547 can augment the response of radiation in FGFR-expressing HNSCC in vivo model systems. FGFR1 and FGFR2 may prove worthy targets for radiosensitization in HNSCC clinical investigations.
Insights
The pan-fibroblast growth factor receptor (FGFR) inhibitor AZD4547 enhances radiation response in head and neck squamous cell carcinoma (HNSCC) models. This combination therapy shows promise for improving HNSCC treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer.
- Fibroblast growth factor receptors (FGFRs) play a role in HNSCC development.
- Targeting FGFRs offers a potential therapeutic strategy for HNSCC.
Purpose of the Study:
- To evaluate the efficacy of AZD4547, a pan-FGFR inhibitor, in combination with radiation therapy for HNSCC.
- To investigate the molecular mechanisms underlying the radiosensitizing effects of AZD4547 in HNSCC.
- To assess the in vitro and in vivo effects of AZD4547 and radiation on HNSCC models.
Main Methods:
- Assessed FGFR1, FGFR2, and FGFR3 expression in HNSCC patient samples, cell lines, and xenografts using RNA in situ hybridization.
- Evaluated in vitro effects of AZD4547 and radiation on cell survival, signaling pathways, apoptosis, autophagy, cell cycle, and DNA damage repair.
- Utilized reverse phase protein array to identify differentially phosphorylated proteins.
- Assessed in vivo tumor responses in cell line and patient-derived xenograft (PDX) models.
Main Results:
- FGFR1, FGFR2, and FGFR3 were expressed in a significant proportion of HNSCC patient samples.
- AZD4547 demonstrated radiosensitizing effects in sensitive HNSCC cell lines, inhibiting p-MAPK signaling.
- The combination therapy involved multifaceted mechanisms, including mTOR pathway inhibition, enhanced autophagy, and apoptosis.
- Significant tumor growth delay was observed in vivo when AZD4547 was combined with radiation in FGFR-expressing HNSCC models.
Conclusions:
- AZD4547 can augment radiation response in FGFR-expressing HNSCC models.
- FGFR1 and FGFR2 are potential therapeutic targets for radiosensitization in HNSCC.
- Further clinical investigations of AZD4547 for HNSCC radiosensitization are warranted.
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