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Supplementary Figure S1. FGFR1 protein expression and FGFR1 gene copy-numbers in HPV-positive and HPV-negative head and neck squamous cell carcinoma. from FGFR1 Is a Potential Prognostic Biomarker and Therapeutic Target in Head and Neck Squamous Cell Carcinoma

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posted on 2023-03-31, 18:26 authored by Koos Koole, Diede Brunen, Pauline M.W. van Kempen, Rob Noorlag, Remco de Bree, Cor Lieftink, Robert J.J. van Es, René Bernards, Stefan M. Willems

(A) FGFR1 protein overexpression and low FGFR1 expression in HPV-positive and HPV-negative head and neck squamous cell carcinoma patients. FGFR1 protein was overexpressed in 82% of HPV-positive and 75% of HPV-negative head and neck squamous cell carcinoma. (B) FGFR1 gene copy-numbers in HPV-positive and HPV-negative head and neck squamous cell carcinoma patients. 3% of FGFR1-overexpressing HPV-negative head and neck squamous cell carcinoma had FGFR1 amplification, 5% had a copy-number gain and 92% had normal gene copy-numbers. All FGFR1-overexpressing HPV-positive head and neck squamous cell carcinoma had normal FGFR1 gene copy-numbers. (C) The Kaplan-Meier overall survival curve for FGFR1 protein overexpression shows no relationship with survival for HPV-positive head and neck squamous cell carcinoma patients (FGFR1 overexpression: 7/33 events, low FGFR1 expression: 2/8 events). Overall survival time was missing for one patient, tissue microarray cores were unavailable for one tumor and two patients were excluded from survival analysis because they were treated with palliative intent. (D) The Kaplan-Meier disease-free survival curve also shows no relationship with survival for HPV-positive head and neck squamous cell carcinoma (FGFR1 overexpression: 10/33 events, low FGFR1 expression: 1/7 events). Disease-free survival time was missing for two patients, tissue microarray cores were unavailable for one tumor and two patients were excluded from survival analysis because they were treated with palliative intent.

Funding

Dutch Cancer Society

History

ARTICLE ABSTRACT

Purpose: FGFR1 is a promising therapeutic target in multiple types of solid tumors, including head and neck squamous cell carcinoma (HNSCC). FGFR inhibitors have shown great therapeutic value in preclinical models. 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: IHC and FISH were applied on tissue microarrays to investigate FGFR1 protein expression and FGFR1 gene copy numbers in 452 HNSCCs. 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 human papillomavirus (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% confidence interval (CI), 1.74–6.90; P = 0.001 and 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 the proliferation of resistant cell lines.Conclusions: Here, we identify high FGFR1 expression as a candidate prognostic biomarker in HPV-negative HNSCC. Furthermore, 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. Clin Cancer Res; 22(15); 3884–93. ©2016 AACR.