FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies

Murry W. Wynes, Trista K. Hinz, Dexiang Gao, Michael Martini, Lindsay A. Marek, Kathryn E. Ware, Michael G. Edwards, Diana Böhm, Sven Perner, Barbara A. Helfrich, Rafal Dziadziuszko, Jacek Jassem, Szymon Wojtylak, Aleksandra Sejda, Joseph M. Gozgit, Paul A. Bunn, D. Ross Camidge, Aik-Choon Tan, Fred R. Hirsch, Lynn E. Heasley

Research output: Contribution to journalArticle

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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. 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.

Original languageEnglish
Pages (from-to)3299-3309
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number12
DOIs
Publication statusPublished - 2014 Jun 15
Externally publishedYes

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Receptor, Fibroblast Growth Factor, Type 1
Gene Dosage
Protein-Tyrosine Kinases
Lung Neoplasms
Histology
Messenger RNA
Atlases
Biomarkers
Neoplasms
Genome
Cell Line
Squamous Cell Neoplasms
Neoplasm Genes
Fibroblast Growth Factor 2
Inhibitory Concentration 50
Adenocarcinoma
Research Design
Ligands
Lung
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wynes, M. W., Hinz, T. K., Gao, D., Martini, M., Marek, L. A., Ware, K. E., ... Heasley, L. E. (2014). FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies. Clinical Cancer Research, 20(12), 3299-3309. https://doi.org/10.1158/1078-0432.CCR-13-3060

FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies. / Wynes, Murry W.; Hinz, Trista K.; Gao, Dexiang; Martini, Michael; Marek, Lindsay A.; Ware, Kathryn E.; Edwards, Michael G.; Böhm, Diana; Perner, Sven; Helfrich, Barbara A.; Dziadziuszko, Rafal; Jassem, Jacek; Wojtylak, Szymon; Sejda, Aleksandra; Gozgit, Joseph M.; Bunn, Paul A.; Camidge, D. Ross; Tan, Aik-Choon; Hirsch, Fred R.; Heasley, Lynn E.

In: Clinical Cancer Research, Vol. 20, No. 12, 15.06.2014, p. 3299-3309.

Research output: Contribution to journalArticle

Wynes, MW, Hinz, TK, Gao, D, Martini, M, Marek, LA, Ware, KE, Edwards, MG, Böhm, D, Perner, S, Helfrich, BA, Dziadziuszko, R, Jassem, J, Wojtylak, S, Sejda, A, Gozgit, JM, Bunn, PA, Camidge, DR, Tan, A-C, Hirsch, FR & Heasley, LE 2014, 'FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies', Clinical Cancer Research, vol. 20, no. 12, pp. 3299-3309. https://doi.org/10.1158/1078-0432.CCR-13-3060
Wynes, Murry W. ; Hinz, Trista K. ; Gao, Dexiang ; Martini, Michael ; Marek, Lindsay A. ; Ware, Kathryn E. ; Edwards, Michael G. ; Böhm, Diana ; Perner, Sven ; Helfrich, Barbara A. ; Dziadziuszko, Rafal ; Jassem, Jacek ; Wojtylak, Szymon ; Sejda, Aleksandra ; Gozgit, Joseph M. ; Bunn, Paul A. ; Camidge, D. Ross ; Tan, Aik-Choon ; Hirsch, Fred R. ; Heasley, Lynn E. / FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 12. pp. 3299-3309.
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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. 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.",
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T1 - FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies

AU - Wynes, Murry W.

AU - Hinz, Trista K.

AU - Gao, Dexiang

AU - Martini, Michael

AU - Marek, Lindsay A.

AU - Ware, Kathryn E.

AU - Edwards, Michael G.

AU - Böhm, Diana

AU - Perner, Sven

AU - Helfrich, Barbara A.

AU - Dziadziuszko, Rafal

AU - Jassem, Jacek

AU - Wojtylak, Szymon

AU - Sejda, Aleksandra

AU - Gozgit, Joseph M.

AU - Bunn, Paul A.

AU - Camidge, D. Ross

AU - Tan, Aik-Choon

AU - Hirsch, Fred R.

AU - Heasley, Lynn E.

PY - 2014/6/15

Y1 - 2014/6/15

N2 - 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.

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