FGFR1 in head and neck squamous cell carcinoma

Purpose:FGFR1 (fibroblast growth factor receptor 1) is a promising therapeutic target in multiple tumors, including head and neck squamous cell carcinoma (HNSCC). However, resistance remains a major setback. In this study we have investigated the prognostic value of FGFR1 expression in HNSCC, the therapeutic relevance of targeting FGFR with AZD4547, and potential resistant mechanisms. Experimental Design:Immunohistochemistry and fluorescence in situ hybridization were applied on tissue microarrays to investigate FGFR1 protein expression and FGFR1 gene copy-numbers in 452 HNSCC. The sensitivity of HNSCC cell lines to AZD4547, either as single or combination treatment with the EGFR-inhibitor gefitinib, was assessed using long-term colony formation assays, short-term viability assays, and biochemical analysis. Results:FGFR1 protein overexpression occurred in 82% (36/44) of HPV-positive HNSCC and 75% (294/392) of HPV-negative HNSCC and relates with poor overall survival and disease-free survival in HPV-negative HNSCC (HR: 3.07; 95% CI: 1.74-6.90; P = 0.001, HR: 1.53; 95% CI: 1.04-2.39; P = 0.033). Moreover, the FGFR1 gene was amplified in 3% (3/110) of HPV-negative HNSCC. Treatment of the high FGFR1 expressing cell line CCL30 with AZD4547 reduced cell proliferation and FGFR signaling. Two FGFR-amplified cell lines, SCC147 and BICR16, were resistant to AZD4547 treatment due to EGFR signaling. Combined AZD4547 and gefitinib treatment synergistically inhibited proliferation of resistant cell lines. Conclusions Here we identify high FGFR1 expression as a candidate prognostic biomarker in HPV- negative HNSCC. We provide a rationale for treating FGFR1-expressing HNSCC with the FGFR inhibitor AZD4547 and for combining AZD4547 and gefitinib in FGFR inhibitor resistant HNSCC patients.

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