Abstract 2832: Fibroblast growth factors in head and neck cancer: Genetic alterations and therapeutic targeting with ponatinib

Abstract

Abstract Background: FGF signaling plays an important role in cancer. Little is known about its involvement in head and neck squamous cell carcinoma (HNSCC). FGFR1 focal amplification and high expression (Freier, Schwaenen et al.), expression of FG-BP (Li et al.) and FGF2 autocrine signalling loops (Marshall et al.) have been described in connection with HNSSC. We therefore examined copy number alterations for several FGFR and FGF-related Genes in 159 patient tissues and cell lines as well as expression levels in 116 patient tissues and 40 cell lines. Based upon our findings we tried a combined FGFR-inhibiton with ponatinib in 5 head and neck cancer-cell lines alone and in combination with gefitinib. Methods: Copy Number Data analysis for 144 patient tissues and cell lines (Nanostring) as well as for 20 cell lines (aCGH) of which 5 were covered by both techniques and showed comparable results. Expression data analysis for 116 tissues and 40 cell lines (Agilent). Viability for 5 cell lines treated with gefitinib and ponatinib alone and in combination. Immunoblotting was performed to deterimed PI3K-AKT and MAPK signaling. Results: Frequent copy number increase could be detected for FGF19 in tissues and cell lines. FGFR1 copy number increase could be seen in only 1 tissue sample, but appeared to be deleted in several samples. High relative expression could be detected for FGFBP1 in tissues and cell lines. Viability testing showed high efficacy in 5/5 cell lines tested for ponatinib but was not solely mediated by AKT or MAPK signaling. Combined treatment with ponatinib and gefitinib was more effective than treatment with either agent alone and synergy was present. Conclusions: FGF signaling is important in Head and Neck Cancer. FGF19 amplification is frequent. We were unable to replicate FGFR1 amplification with only one tissue showing FGFR1 copy number increase. High expression levels could be shown for FGFBP1, providing an alternative hypothesis for explaining the efficacy of FGF2 inhibition as previously shown (Marshall et. al.). Ponatinib is effective as a single agent on HNSSC cell line models and shows synergistic effect in combination with gefitinib. It is promising to evaluate FGF pathway inhibition (e.g. with ponatinib) in its ability to overcome EGFR-inhibitor resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2832. doi:1538-7445.AM2012-2832