Abstract 2929: Radiosensitization of head and neck cancer by FGFR inhibition

Abstract

Abstract Objective: Fibroblast growth factor receptors are frequently amplified or overexpressed in head and neck squamous cell carcinomas (HNSCC). We assessed the potential of a selective FGFR-kinase inhibitor, AZD4547, to act as a radiosensitizer in head and neck cancer cell lines and xenografts. Methods: A panel of head and neck cancer (n=10) and normal oral mucosa (HTE) cell lines were screened for FGFR1, 2, and 3 gene copy number, RNA expression, and protein. Sensitivity to the FGFR inhibitor AZD4547, alone or in combination with radiation, was assessed using proliferation and clonogenic survival assays. Putative mechanisms of radiosensitization were investigated by immunoblot and by assessing for DNA repair capacity, cell cycle effects, apoptosis, senescence, and autophagy. Tumor response of cell line xenografts and patient derived xenografts was assessed in vivo. Results: Cells demonstrated varying responses to FGFR inhibition but this did not correlate with FGFR gene copy number, mRNA expression, or protein expression. Three cell lines which responded to AZD4547 alone (CCL30, Tu-138, and SCC6) were selected for further investigation. TU-138 and CCL30 featured high FGFR expression and were radiosensitized by AZD4547 in vitro. SCC6 was not. Cell lines which were insensitive to FGFR inhibition (including HTE) did not demonstrate radiosensitization by AZD4547. In the sensitive cell lines, enhanced p-MAPK inhibition was seen in a time-dependent manner following drug treatment. When added to radiation, AZD4547 resulted in increased apoptosis, autophagy, and senescence but did not alter the kinetics of DNA repair as assessed by resolution of gH2AX foci. No difference in the cell cycle distribution for irradiated cells treated with or without the addition of AZD4547 was seen. Treatment of two in vivo tumor xenografts with AZD4547 and radiation showed significant delay in tumor growth compared to treatment with radiation or drug alone. Conclusion: Our findings indicate that AZD4547 can augment the response of FGFR expressing HNSCC to radiation both in vitro and in vivo. Improved approaches to identify tumors most likely to benefit from FGFR inhibition could enable the selection of patients for combination therapy and has the potential to improve outcomes in these difficult to treat cancers. Citation Format: Gopika SenthilKumar, Margot Miller, Michael Fisher, Sean Brennan, Saakshi Kaushik, Lindsey Able, Paul M. Harari, Gopal Iyer, Randall J. Kimple, Andrew M. Baschnagel. Radiosensitization of head and neck cancer by FGFR inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2929.