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FGFR1 Is a Potential Prognostic Biomarker and Therapeutic Target in Head and Neck Squamous Cell Carcinoma.
Clin Cancer Res. 2016 08 01; 22(15):3884-93.CC

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.

Authors+Show Affiliations

Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands.Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.Department of Otorhinolaryngology - Head and Neck Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands.Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands.Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.Department of Head and Neck Surgical Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands.Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. s.m.willems-4@umcutrecht.nl.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26936917

Citation

Koole, Koos, et al. "FGFR1 Is a Potential Prognostic Biomarker and Therapeutic Target in Head and Neck Squamous Cell Carcinoma." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 22, no. 15, 2016, pp. 3884-93.
Koole K, Brunen D, van Kempen PM, et al. FGFR1 Is a Potential Prognostic Biomarker and Therapeutic Target in Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2016;22(15):3884-93.
Koole, K., Brunen, D., van Kempen, P. M., Noorlag, R., de Bree, R., Lieftink, C., van Es, R. J., Bernards, R., & Willems, S. M. (2016). FGFR1 Is a Potential Prognostic Biomarker and Therapeutic Target in Head and Neck Squamous Cell Carcinoma. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 22(15), 3884-93. https://doi.org/10.1158/1078-0432.CCR-15-1874
Koole K, et al. FGFR1 Is a Potential Prognostic Biomarker and Therapeutic Target in Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2016 08 1;22(15):3884-93. PubMed PMID: 26936917.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FGFR1 Is a Potential Prognostic Biomarker and Therapeutic Target in Head and Neck Squamous Cell Carcinoma. AU - Koole,Koos, AU - Brunen,Diede, AU - van Kempen,Pauline M W, AU - Noorlag,Rob, AU - de Bree,Remco, AU - Lieftink,Cor, AU - van Es,Robert J J, AU - Bernards,René, AU - Willems,Stefan M, Y1 - 2016/03/02/ PY - 2015/08/04/received PY - 2016/02/23/accepted PY - 2016/3/4/entrez PY - 2016/3/5/pubmed PY - 2018/1/13/medline SP - 3884 EP - 93 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 22 IS - 15 N2 - 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. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/26936917/FGFR1_Is_a_Potential_Prognostic_Biomarker_and_Therapeutic_Target_in_Head_and_Neck_Squamous_Cell_Carcinoma_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=26936917 DB - PRIME DP - Unbound Medicine ER -