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FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2014 Jun 15; Vol. 20 (12), pp. 3299-309. Date of Electronic Publication: 2014 Apr 25. - Publication Year :
- 2014
-
Abstract
- 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.<br />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.<br />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.<br />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.<br /> (©2014 American Association for Cancer Research.)
- Subjects :
- Adenocarcinoma drug therapy
Adenocarcinoma genetics
Adenocarcinoma metabolism
Blotting, Western
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Squamous Cell drug therapy
Carcinoma, Squamous Cell genetics
Carcinoma, Squamous Cell metabolism
Cell Proliferation
Cohort Studies
Follow-Up Studies
Gene Amplification
Humans
Imidazoles pharmacology
Immunoenzyme Techniques
Lung Neoplasms drug therapy
Lung Neoplasms genetics
Lung Neoplasms metabolism
Neoplasm Staging
Pyridazines pharmacology
RNA, Messenger genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Tumor Cells, Cultured
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung metabolism
Drug Resistance, Neoplasm genetics
Gene Dosage
Protein Kinase Inhibitors pharmacology
Receptor, Fibroblast Growth Factor, Type 1 genetics
Receptor, Fibroblast Growth Factor, Type 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 20
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 24771645
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-13-3060