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FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers.
Clin Cancer Res. 2015 Oct 01; 21(19):4356-64.CC

Abstract

PURPOSE

FGFR1 copy-number gain (CNG) occurs in head and neck squamous cell cancers (HNSCC) and is used for patient selection in FGFR-specific inhibitor clinical trials. This study explores FGFR1 mRNA and protein levels in HNSCC cell lines, primary tumors, and patient-derived xenografts (PDX) as predictors of sensitivity to the FGFR inhibitor, NVP-BGJ398.

EXPERIMENTAL DESIGN

FGFR1 status, expression levels, and BGJ398 sensitive growth were measured in 12 HNSCC cell lines. Primary HNSCCs (n = 353) were assessed for FGFR1 CNG and mRNA levels, and HNSCC TCGA data were interrogated as an independent sample set. HNSCC PDXs (n = 39) were submitted to FGFR1 copy-number detection and mRNA assays to identify putative FGFR1-dependent tumors.

RESULTS

Cell line sensitivity to BGJ398 is associated with FGFR1 mRNA and protein levels, not FGFR1 CNG. Thirty-one percent of primary HNSCC tumors expressed FGFR1 mRNA, 18% exhibited FGFR1 CNG, 35% of amplified tumors were also positive for FGFR1 mRNA. This relationship was confirmed with the TCGA dataset. Using high FGFR1 mRNA for selection, 2 HNSCC PDXs were identified, one of which also exhibited FGFR1 CNG. The nonamplified tumor with high mRNA levels exhibited in vivo sensitivity to BGJ398.

CONCLUSIONS

FGFR1 expression associates with BGJ398 sensitivity in HNSCC cell lines and predicts tyrosine kinase inhibitor sensitivity in PDXs. Our results support FGFR1 mRNA or protein expression, rather than FGFR1 CNG as a predictive biomarker for the response to FGFR inhibitors in a subset of patients suffering from HNSCC.

Authors+Show Affiliations

Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.Department of Internal Medicine, Philipps-University of Marburg, Marburg, Germany.Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.Department of Otorhinolaryngology/Head and Neck Surgery, University of Bonn, Bonn, Germany.Department of Otorhinolaryngology/Head and Neck Surgery, University of Bonn, Bonn, Germany.Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Department of Otorhinolaryngology/Head and Neck Surgery, University of Bonn, Bonn, Germany.Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Otolaryngology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.Department of Internal Medicine, Philipps-University of Marburg, Marburg, Germany. VA Eastern Colorado Healthcare System, Denver, Colorado.Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. sven.perner1972@googlemail.com.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

26015511

Citation

Göke, Friederike, et al. "FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 21, no. 19, 2015, pp. 4356-64.
Göke F, Franzen A, Hinz TK, et al. FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers. Clin Cancer Res. 2015;21(19):4356-64.
Göke, F., Franzen, A., Hinz, T. K., Marek, L. A., Yoon, P., Sharma, R., Bode, M., von Maessenhausen, A., Lankat-Buttgereit, B., Göke, A., Golletz, C., Kirsten, R., Boehm, D., Vogel, W., Kleczko, E. K., Eagles, J. R., Hirsch, F. R., Van Bremen, T., Bootz, F., ... Perner, S. (2015). FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 21(19), 4356-64. https://doi.org/10.1158/1078-0432.CCR-14-3357
Göke F, et al. FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers. Clin Cancer Res. 2015 Oct 1;21(19):4356-64. PubMed PMID: 26015511.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers. AU - Göke,Friederike, AU - Franzen,Alina, AU - Hinz,Trista K, AU - Marek,Lindsay A, AU - Yoon,Petros, AU - Sharma,Rakesh, AU - Bode,Maike, AU - von Maessenhausen,Anne, AU - Lankat-Buttgereit,Brigitte, AU - Göke,Antonia, AU - Golletz,Carsten, AU - Kirsten,Robert, AU - Boehm,Diana, AU - Vogel,Wenzel, AU - Kleczko,Emily K, AU - Eagles,Justin R, AU - Hirsch,Fred R, AU - Van Bremen,Tobias, AU - Bootz,Friedrich, AU - Schroeck,Andreas, AU - Kim,Jihye, AU - Tan,Aik-Choon, AU - Jimeno,Antonio, AU - Heasley,Lynn E, AU - Perner,Sven, Y1 - 2015/05/26/ PY - 2014/12/28/received PY - 2015/05/11/accepted PY - 2015/5/28/entrez PY - 2015/5/28/pubmed PY - 2016/7/12/medline SP - 4356 EP - 64 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 21 IS - 19 N2 - PURPOSE: FGFR1 copy-number gain (CNG) occurs in head and neck squamous cell cancers (HNSCC) and is used for patient selection in FGFR-specific inhibitor clinical trials. This study explores FGFR1 mRNA and protein levels in HNSCC cell lines, primary tumors, and patient-derived xenografts (PDX) as predictors of sensitivity to the FGFR inhibitor, NVP-BGJ398. EXPERIMENTAL DESIGN: FGFR1 status, expression levels, and BGJ398 sensitive growth were measured in 12 HNSCC cell lines. Primary HNSCCs (n = 353) were assessed for FGFR1 CNG and mRNA levels, and HNSCC TCGA data were interrogated as an independent sample set. HNSCC PDXs (n = 39) were submitted to FGFR1 copy-number detection and mRNA assays to identify putative FGFR1-dependent tumors. RESULTS: Cell line sensitivity to BGJ398 is associated with FGFR1 mRNA and protein levels, not FGFR1 CNG. Thirty-one percent of primary HNSCC tumors expressed FGFR1 mRNA, 18% exhibited FGFR1 CNG, 35% of amplified tumors were also positive for FGFR1 mRNA. This relationship was confirmed with the TCGA dataset. Using high FGFR1 mRNA for selection, 2 HNSCC PDXs were identified, one of which also exhibited FGFR1 CNG. The nonamplified tumor with high mRNA levels exhibited in vivo sensitivity to BGJ398. CONCLUSIONS: FGFR1 expression associates with BGJ398 sensitivity in HNSCC cell lines and predicts tyrosine kinase inhibitor sensitivity in PDXs. Our results support FGFR1 mRNA or protein expression, rather than FGFR1 CNG as a predictive biomarker for the response to FGFR inhibitors in a subset of patients suffering from HNSCC. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/26015511/FGFR1_Expression_Levels_Predict_BGJ398_Sensitivity_of_FGFR1_Dependent_Head_and_Neck_Squamous_Cell_Cancers_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=26015511 DB - PRIME DP - Unbound Medicine ER -