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Title: Somatic Mutations and Splicing Variants of Focal Adhesion Kinase in Non-Small Cell Lung Cancer
Author: Bo Zhou, Gui-Zhen Wang, Zhe-Sheng Wen, Yong-Chun Zhou, Yun-Chao Huang, Ying Chen, Guang-Biao Zhou
Abstract: Background Overexpression of focal adhesion kinase (FAK) has been reported in lung cancer, but the somatic mutations and alternative splicing variants of this nonreceptor tyrosine kinase remain to be investigated. Methods FAK in 91 lung cancer patients was sequenced using genomic DNA and cDNA samples of tumor and paired normal lung tissues as templates, and the RNA-seq data of The Cancer Genome Atlas (TCGA) data set were assessed. The biological functions of abnormal FAK transcripts and their response to FAK inhibitors were analyzed in eight cell lines using tyrosine kinase activity assay, trypan blue exclusion assay, MTT (3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide) assay, and transwell assay. Results We identified an internal tandem duplication (ITD), an A1004S point mutation, an exon 5–27 deletion (ΔE5-27) truncation variant, and four FAK6,7 splicing variants (containing exons for Boxes 6 and 7) in seven (7.7%) patients. Smokers had more FAK abnormalities than nonsmokers. In FAK-ITD, the sequence encoding the C-terminal of the FERM domain and kinase domain was duplicated in-frame and produced a protein product with elevated autophosphorylation and sensitivity to FAK inhibitors. FAK6,7 was detected in the tumor but not counterpart normal lung tissues of four (4.4%) patients. In TCGA RNA-seq data, Box 6 and/or Box 7 (Box 6/7)–containing FAK variants were positive in 42 (8.3%) of 508 lung adenocarcinomas (LUADs) and 37 (7.4%) of 501 lung squamous cell carcinomas, and smokers had higher expression of Box 6/7 (+) FAK than reformed or nonsmokers with LUAD. FAK6,7 promoted cell proliferation and migration, exhibited increased autophosphorylation, and was more sensitive to FAK inhibitor compared with wild-type FAK. Conclusions Somatic mutations and splicing variants of FAK may have a role in lung carcinogenesis and represent potential biomarkers for FAK-targeted therapies.
Corresponding author: Guang-Biao Zhou
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PubYear: 2018
Volume: 110
Issue: 2
Page: Article No. djx157
Journal: JNCI-Journal of the National Cancer Institute
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URL: https://academic.oup.com/jnci/article/doi/10.1093/jnci/djx157/4565750