Fer Protein-Tyrosine Kinase as a Potential Therapeutic Target in Lung Cancer

Abstract

Fer is a ubiquitously expressed non-receptor protein-tyrosine kinase that regulates normal physiology through signaling in a variety of cell types. Fer signals downstream of growth factor receptors frequently activated or amplified in human cancers and Fer has been identified as a positive regulator of cancer progression in the prostate and liver. Epidermal growth factor (EGF) receptor (EGFR) is frequently activated due to gene amplification or gain-of-function mutations in non-small cell lung carcinomas (NSCLC) leading to aggressive tumours that frequently metastasize. Since EGFR activates Fer, I tested whether Fer participates in EGFR-driven NSCLC cell migration, tumour progression and metastasis. Here, I show that Fer is expressed in cell lines derived from both normal lung epithelia and NSCLC and is activated following EGF treatment of NSCLC cells. To probe Fer function we used a lentiviral shRNA system to achieve stable knock-down (KD) of Fer in H1299 cells. Compared to control cells, Fer KD cells displayed a significant reduction in EGF-induced cell migration and invasion which correlated with reduced phosphorylation of the guanine nucleotide exchange factor Vav2. Consistent with Vav2 phosphorylation promoting Rac activation, we observed reduced localization of active, GTP- bound Rac1 to the leading edge of Fer KD cells treated with EGF. Tumour xenograft experiments were performed to test the role of Fer in NSCLC tumour progression and metastasis in immune compromised mice. Growth of primary tumours was normal, despite efficient Fer silencing in vivo. Interestingly, fewer spontaneous lung metastases were observed from subcutaneous Fer KD tumours compared to control. However, no differences were observed in lung seeding efficiency in experimental metastasis assays, suggesting that Fer may play a role in early stages of metastasis. Together, this study identifies Fer as a potential new therapeutic target for the treatment of EGFR-driven lung cancer metastasis.