Abstract 1094: Combining the pan-FGFR inhibitor AZD4547 with radiation in lung and head and neck squamous cell carcinoma

Abstract

Abstract The fibroblast growth factor receptors (FGFR1, FGR2, FRG3, FGR4) are frequently altered or overexpressed in both lung and head and neck squamous cell carcinomas (SCC). Amplification of FGFR1 has been reported to be as high as 22% in lung SCC and 17% in head and neck SCC (HNSCC). FGFRs have been identified as a potential therapeutic target in lung and head and neck cancers. In addition, FGFRs activate multiple pathways involved in the radiation response including RAS/RAF/MAPK, PI3K/AKT and STAT. AZD4547 is a potent and selective tyrosine kinase inhibitor of the FGFR family and is currently being investigated in clinical trials. Since a substantial portion of lung cancer and HNSCC patients are treated with radiotherapy, we examined the anti-tumor effects of AZD4547 in combination with radiation in both lung and head and neck cancer model systems. FGFR protein and RNA expression and cell proliferation with AZD4547 were evaluated in 8 lung and 8 head and neck cancer cell lines. Clonogenic survival assays were performed on 4 lung and 4 head and neck cancer cell lines and xenograft experiments were performed on one HNSCC cell line. These cell lines demonstrated varying levels of FGFR1, 2 and 3 protein and RNA expression. The half maximal inhibitory concentration (IC50) of AZD4547 in these cell lines ranged from 0.05 to 128 uM. Sensitivity to AZD4547 did not correlate directly with protein or RNA expression. In vitro clonogenic survival assays showed limited effects of combining AZD4547 with radiation. However, significant tumor growth delay was observed with the combination of radiation and AZD4547 compared to radiation or drug alone in the SCC1483 FGFR2 expressing HNSCC xenograft model. These findings suggest that AZD4547 can augment the response of radiation in an in vivo model system. Further studies are underway to test these findings in additional cell lines including FGFR dependent amplified cancer cell lines. Citation Format: Andrew M. Baschnagel, Chunrong Li, Alecia M. Morgan, Sean R. Brennan, Kalley A. Russo, Paul M. Harari. Combining the pan-FGFR inhibitor AZD4547 with radiation in lung and head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1094. doi:10.1158/1538-7445.AM2017-1094