Abstract
Epidermal growth factor receptor (EGFR) is frequently amplified or mutated in non-small cell lung cancer (NSCLC). Although Fer protein-tyrosine kinase signals downstream of EGFR, its role in NSCLC tumor progression has not been reported. Here, Fer kinase was elevated in NSCLC tumors compared to normal lung epithelium. EGFR signaling in NSCLC cells fosters rapid Fer activation and increased localization to lamellipodia. Stable silencing of Fer in H1299 lung adenocarcinoma cells (Fer KD) caused impaired EGFR-induced lamellipodia formation compared to control cells. Fer KD NSCLC cells showed reduced Vav2 tyrosine phosphorylation that was correlated with direct Fer-mediated phosphorylation of Vav2 on tyrosine-172, which was previously reported to increase the guanine nucleotide exchange factor activity of Vav2. Indeed, Fer KD cells displayed defects in Rac-GTP localization to lamellipodia, cell migration, and cell invasion in vitro. To test the role of Fer in NSCLC progression and metastasis, control and Fer KD cells were grown as subcutaneous tumors in mice. Although Fer was not required for tumor growth, Fer KD tumor-bearing mice had significantly fewer numbers of spontaneous metastases. Combined, these data demonstrate that Fer kinase is elevated in NSCLC tumors and is important for cellular invasion and metastasis. Fer protein-tyrosine kinase is a potential therapeutic target in metastatic lung cancer. Mol Cancer Res; 11(8); 952-63. ©2013 AACR.
Highlights
Non–small cell lung carcinoma (NSCLC) is the most common form of lung cancer and the leading cause of cancer-related deaths worldwide
No differences were observed in levels of Vav2 between genotypes, ferDR/DR mouse embryonic fibroblasts (MEF) showed reduced Vav2 pY upon EGF treatment compared with that observed in ferþ/þ MEFs (Fig. 4B, second and fourth panels). These results indicate that EGF receptor (EGFR)-induced Vav2 pY is partially dependent on Fer kinase in NSCLC and MEFs
We provide evidence that Fer propagates EGFR signals that enhance cell migration, invasion, and tumor metastasis
Summary
Non–small cell lung carcinoma (NSCLC) is the most common form of lung cancer and the leading cause of cancer-related deaths worldwide. A subset of NSCLC's acquire increased copy number or gain-of-function mutations in EGF receptor (EGFR) leading to constitutive EGFR signaling to pathways controlling cell growth, survival, and motility [1]. Patients with lung cancer with activating EGFR mutations who are treated with EGFR inhibitors frequently show a positive initial response but eventually relapse due to Authors' Affiliations: Departments of 1Biomedical and Molecular Sciences and 2Pathology & Molecular Medicine, 3Division of Cancer Biology & Genetics, Queen's University, Kingston, Ontario, Canada. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
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