FGFR1 mRNA and Protein Expression, not Gene Copy Number, Predict FGFR TKI Sensitivity across All Lung Cancer Histologies
FGFR1 gene copy number (GCN) is being evaluated as a biomarker for FGFR tyrosine kinase inhibitor (TKI) response in squamous cell lung cancers (SCC). The exclusive use of FGFR1 GCN for predicting FGFR TKI sensitivity assumes increased GCN is the only mechanism for biologically relevant increases in...
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Published in | Clinical cancer research Vol. 20; no. 12; pp. 3299 - 3309 |
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Main Authors | , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Philadelphia, PA
American Association for Cancer Research
15.06.2014
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Abstract | FGFR1 gene copy number (GCN) is being evaluated as a biomarker for FGFR tyrosine kinase inhibitor (TKI) response in squamous cell lung cancers (SCC). The exclusive use of FGFR1 GCN for predicting FGFR TKI sensitivity assumes increased GCN is the only mechanism for biologically relevant increases in FGFR1 signaling. Herein, we tested whether FGFR1 mRNA and protein expression may serve as better biomarkers of FGFR TKI sensitivity in lung cancer.
Histologically diverse lung cancer cell lines were submitted to assays for ponatinib sensitivity, a potent FGFR TKI. A tissue microarray composed of resected lung tumors was submitted to FGFR1 GCN, and mRNA analyses and the results were validated with The Cancer Genome Atlas (TCGA) lung cancer data.
Among 58 cell lines, 14 exhibited ponatinib sensitivity (IC50 values ≤ 50 nmol/L) that correlated with FGFR1 mRNA and protein expression, but not with FGFR1 GCN or histology. Moreover, ponatinib sensitivity associated with mRNA expression of the ligands, FGF2 and FGF9. In resected tumors, 22% of adenocarcinomas and 28% of SCCs expressed high FGFR1 mRNA. Importantly, only 46% of SCCs with increased FGFR1 GCN expressed high mRNA. Lung cancer TCGA data validated these findings and unveiled overlap of FGFR1 mRNA positivity with KRAS and PIK3CA mutations.
FGFR1 dependency is frequent across various lung cancer histologies, and FGFR1 mRNA may serve as a better biomarker of FGFR TKI response in lung cancer than FGFR1 GCN. The study provides important and timely insight into clinical testing of FGFR TKIs in lung cancer and other solid tumor types. |
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AbstractList | FGFR1 gene copy number (GCN) is being evaluated as a biomarker for FGFR tyrosine kinase inhibitor (TKI) response in squamous cell lung cancers (SCC). The exclusive use of FGFR1 GCN for predicting FGFR TKI sensitivity assumes increased GCN is the only mechanism for biologically relevant increases in FGFR1 signaling. Herein, we tested whether FGFR1 mRNA and protein expression may serve as better biomarkers of FGFR TKI sensitivity in lung cancer.
Histologically diverse lung cancer cell lines were submitted to assays for ponatinib sensitivity, a potent FGFR TKI. A tissue microarray composed of resected lung tumors was submitted to FGFR1 GCN, and mRNA analyses and the results were validated with The Cancer Genome Atlas (TCGA) lung cancer data.
Among 58 cell lines, 14 exhibited ponatinib sensitivity (IC50 values ≤ 50 nmol/L) that correlated with FGFR1 mRNA and protein expression, but not with FGFR1 GCN or histology. Moreover, ponatinib sensitivity associated with mRNA expression of the ligands, FGF2 and FGF9. In resected tumors, 22% of adenocarcinomas and 28% of SCCs expressed high FGFR1 mRNA. Importantly, only 46% of SCCs with increased FGFR1 GCN expressed high mRNA. Lung cancer TCGA data validated these findings and unveiled overlap of FGFR1 mRNA positivity with KRAS and PIK3CA mutations.
FGFR1 dependency is frequent across various lung cancer histologies, and FGFR1 mRNA may serve as a better biomarker of FGFR TKI response in lung cancer than FGFR1 GCN. The study provides important and timely insight into clinical testing of FGFR TKIs in lung cancer and other solid tumor types. Purpose: FGFR1 gene copy number (GCN) is being evaluated as a biomarker for FGFR tyrosine kinase inhibitor (TKI) response in squamous cell lung cancers (SCC). The exclusive use of FGFR1 GCN for predicting FGFR TKI sensitivity assumes increased GCN is the only mechanism for biologically relevant increases in FGFR1 signaling. Herein, we tested whether FGFR1 mRNA and protein expression may serve as better biomarkers of FGFR TKI sensitivity in lung cancer. Experimental Design: Histologically diverse lung cancer cell lines were submitted to assays for ponatinib sensitivity, a potent FGFR TKI. A tissue microarray composed of resected lung tumors was submitted to FGFR1 GCN, and mRNA analyses and the results were validated with The Cancer Genome Atlas (TCGA) lung cancer data. Results: Among 58 cell lines, 14 exhibited ponatinib sensitivity (IC50 values ≤ 50 nmol/L) that correlated with FGFR1 mRNA and protein expression, but not with FGFR1 GCN or histology. Moreover, ponatinib sensitivity associated with mRNA expression of the ligands, FGF2 and FGF9. In resected tumors, 22% of adenocarcinomas and 28% of SCCs expressed high FGFR1 mRNA. Importantly, only 46% of SCCs with increased FGFR1 GCN expressed high mRNA. Lung cancer TCGA data validated these findings and unveiled overlap of FGFR1 mRNA positivity with KRAS and PIK3CA mutations. Conclusions: FGFR1 dependency is frequent across various lung cancer histologies, and FGFR1 mRNA may serve as a better biomarker of FGFR TKI response in lung cancer than FGFR1 GCN. The study provides important and timely insight into clinical testing of FGFR TKIs in lung cancer and other solid tumor types. Clin Cancer Res; 20(12); 3299–309. ©2014 AACR. |
Author | CAMIDGE, D. Ross TAN, Aik-Choon WOJTYLAK, Szymon PERNER, Sven HEASLEY, Lynn E DZIADZIUSZKO, Rafal HELFRICH, Barbara A WARE, Kathryn E BUNN, Paul A HINZ, Trista K DEXIANG GAO BÖHM, Diana JASSEM, Jacek GOZGIT, Joseph M WYNES, Murry W SEJDA, Aleksandra MARTINI, Michael MAREK, Lindsay A EDWARDS, Michael G HIRSCH, Fred R |
AuthorAffiliation | 4 Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO 3 Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 7 ARIAD Pharmaceuticals, Inc., Cambridge, MA 2 Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 5 Medical University of Gdańsk, Poland 1 Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 6 Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Germany |
AuthorAffiliation_xml | – name: 3 Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO – name: 6 Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Germany – name: 2 Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO – name: 4 Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO – name: 1 Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO – name: 7 ARIAD Pharmaceuticals, Inc., Cambridge, MA – name: 5 Medical University of Gdańsk, Poland |
Author_xml | – sequence: 1 givenname: Murry W surname: WYNES fullname: WYNES, Murry W organization: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States – sequence: 2 givenname: Trista K surname: HINZ fullname: HINZ, Trista K organization: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States – sequence: 3 givenname: Rafal surname: DZIADZIUSZKO fullname: DZIADZIUSZKO, Rafal organization: Medical University of Gdan'sk, Poland – sequence: 4 givenname: Jacek surname: JASSEM fullname: JASSEM, Jacek organization: Medical University of Gdan'sk, Poland – sequence: 5 givenname: Szymon surname: WOJTYLAK fullname: WOJTYLAK, Szymon organization: Medical University of Gdan'sk, Poland – sequence: 6 givenname: Aleksandra surname: SEJDA fullname: SEJDA, Aleksandra organization: Medical University of Gdan'sk, Poland – sequence: 7 givenname: Joseph M surname: GOZGIT fullname: GOZGIT, Joseph M organization: ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts, United States – sequence: 8 givenname: Paul A surname: BUNN fullname: BUNN, Paul A organization: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States – sequence: 9 givenname: D. Ross surname: CAMIDGE fullname: CAMIDGE, D. Ross organization: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States – sequence: 10 givenname: Aik-Choon surname: TAN fullname: TAN, Aik-Choon organization: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States – sequence: 11 givenname: Fred R surname: HIRSCH fullname: HIRSCH, Fred R organization: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States – sequence: 12 givenname: Lynn E surname: HEASLEY fullname: HEASLEY, Lynn E organization: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States – sequence: 13 surname: DEXIANG GAO fullname: DEXIANG GAO organization: Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States – sequence: 14 givenname: Michael surname: MARTINI fullname: MARTINI, Michael organization: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States – sequence: 15 givenname: Lindsay A surname: MAREK fullname: MAREK, Lindsay A organization: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States – sequence: 16 givenname: Kathryn E surname: WARE fullname: WARE, Kathryn E organization: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States – sequence: 17 givenname: Michael G surname: EDWARDS fullname: EDWARDS, Michael G organization: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States – sequence: 18 givenname: Diana surname: BÖHM fullname: BÖHM, Diana organization: Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany – sequence: 19 givenname: Sven surname: PERNER fullname: PERNER, Sven organization: Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany – sequence: 20 givenname: Barbara A surname: HELFRICH fullname: HELFRICH, Barbara A organization: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States |
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Keywords | Lung disease Respiratory disease Tyrosine kinase inhibitor Copy number Lung cancer Biological marker Histology Malignant tumor Gene expression Bronchopulmonary Protein Sensitivity Messenger RNA Bronchus disease Predictive factor Fibroblast growth factor receptor 1 Cancer |
Language | English |
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Snippet | FGFR1 gene copy number (GCN) is being evaluated as a biomarker for FGFR tyrosine kinase inhibitor (TKI) response in squamous cell lung cancers (SCC). The... Purpose: FGFR1 gene copy number (GCN) is being evaluated as a biomarker for FGFR tyrosine kinase inhibitor (TKI) response in squamous cell lung cancers (SCC).... |
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SubjectTerms | Adenocarcinoma - drug therapy Adenocarcinoma - genetics Adenocarcinoma - metabolism Biological and medical sciences Blotting, Western Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - metabolism Cell Proliferation Cohort Studies Drug Resistance, Neoplasm - genetics Follow-Up Studies Gene Amplification Gene Dosage Humans Imidazoles - pharmacology Immunoenzyme Techniques Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - metabolism Medical sciences Neoplasm Staging Pneumology Protein Kinase Inhibitors - pharmacology Pyridazines - pharmacology Real-Time Polymerase Chain Reaction Receptor, Fibroblast Growth Factor, Type 1 - genetics Receptor, Fibroblast Growth Factor, Type 1 - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics Signal Transduction Tumor Cells, Cultured Tumors of the respiratory system and mediastinum |
Title | FGFR1 mRNA and Protein Expression, not Gene Copy Number, Predict FGFR TKI Sensitivity across All Lung Cancer Histologies |
URI | https://www.ncbi.nlm.nih.gov/pubmed/24771645 https://pubmed.ncbi.nlm.nih.gov/PMC4062100 |
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