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
Authors' Affiliations: Departments of Medicine, Pathology, Craniofacial Biology, and Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado; ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts; Medical University of Gdańsk, Poland; and Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
Authors' Affiliations: Departments of Medicine, Pathology, Craniofacial Biology, and Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado; ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts; Medical University of Gdańsk, Poland; and Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, GermanyAuthors' Affiliations: Departments of Medicine, Pathology, Craniofacial Biology, and Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado; ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts; Medical University of Gdańsk, Poland; and Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany
Clin Cancer Res. 2014 Jun 15;20(12):3299-309. doi: 10.1158/1078-0432.CCR-13-3060. Epub 2014 Apr 25.
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.
FGFR1基因拷贝数（GCN）正被评估为肺鳞状细胞癌（SCC）中FGFR酪氨酸激酶抑制剂（TKI）反应的生物标志物。仅使用FGFR1 GCN来预测FGFR TKI敏感性假定GCN增加是FGFR1信号生物学相关增加的唯一机制。在此，我们测试了FGFR1 mRNA和蛋白表达是否可作为肺癌中FGFR TKI敏感性更好的生物标志物。
将组织学类型多样的肺癌细胞系进行针对强效FGFR TKI泊那替尼敏感性的检测。将由切除的肺肿瘤组成的组织芯片进行FGFR1 GCN和mRNA分析，结果用癌症基因组图谱（TCGA）肺癌数据进行验证。
在58个细胞系中，14个表现出泊那替尼敏感性（IC50值≤50 nmol/L），这与FGFR1 mRNA和蛋白表达相关，但与FGFR1 GCN或组织学无关。此外，泊那替尼敏感性与配体FGF2和FGF9的mRNA表达相关。在切除的肿瘤中，22%的腺癌和28%的SCC表达高水平FGFR1 mRNA。重要的是，FGFR1 GCN增加的SCC中只有46%表达高水平mRNA。肺癌TCGA数据验证了这些发现，并揭示了FGFR1 mRNA阳性与KRAS和PIK3CA突变的重叠。
FGFR1依赖性在各种肺癌组织学类型中都很常见，并且FGFR1 mRNA可能比FGFR1 GCN更适合作为肺癌中FGFR TKI反应的生物标志物。该研究为肺癌及其他实体瘤类型中FGFR TKIs的临床检测提供了重要且及时的见解。
