Abstract
Lung cancer outcomes remain poor despite the identification of several potential therapeutic targets. The EPHB4 receptor tyrosine kinase (RTK) has recently emerged as an oncogenic factor in many cancers, including lung cancer. Mutations of EPHB4 in lung cancers have previously been identified, though their significance remains unknown. Here, we report the identification of novel EPHB4 mutations that lead to putative structural alterations as well as increased cellular proliferation and motility. We also conducted a bioinformatic analysis of these mutations to demonstrate that they are mutually exclusive from other common RTK variants in lung cancer, that they correspond to analogous sites of other RTKs’ variations in cancers, and that they are predicted to be oncogenic based on biochemical, evolutionary, and domain-function constraints. Finally, we show that EPHB4 mutations can induce broad changes in the kinome signature of lung cancer cells. Taken together, these data illuminate the role of EPHB4 in lung cancer and further identify EPHB4 as a potentially important therapeutic target.
Highlights
Receptor tyrosine kinases (RTKs) are frequently altered in lung cancer
No non-synonymous (NS) mutations were detected in cell lines; a number of synonymous and NS variations were found in lung tissues Notably, eight NS EPHB4 mutations were detected: one (A230V) in an extracellular linker region; two (A371V and P381S) in the first extracellular fibronectin III repeat; two (W534* and E536K) in the extracellular juxtamembrane domain; two (G723S and A742V) in the tyrosine kinase domain; and one (P881S) in an intracellular linker region just carboxy-terminal to the tyrosine kinase domain
We have reported a series of novel non-synonymous mutations in the EPHB4 receptor tyrosine kinase with associated putative structural alterations and effects on kinome signaling
Summary
Receptor tyrosine kinases (RTKs) are frequently altered in lung cancer. EGFR, MET, RON, KIT, and EPH family members are commonly overexpressed or mutated, contributing to tumorigenesis in the lung. A mutation in EPHA2 causes constitutive kinase activation in and contributes to the development of lung squamous cell carcinoma (SCC)[1], while mutations in EPHB6 appear to have significant pro-metastatic effects in non-small cell lung cancer (NSCLC) cells[2]. EPHB4 is overexpressed and amplified in several lung cancer subtypes and is necessary for the growth of lung adenocarcinoma xenografts in mice[6] This appears to be mediated by Akt and Src signaling downstream. Non-synonymous mutations in the EPHB4 gene have been identified, and many occur in human tumor tissues and cell lines. The functional and structural effects of EPHB4 mutations and their potential significance in the context of lung cancer remain essentially unknown. The downstream signaling patterns of wild-type and mutated EPHB4 in lung cancer are reported using high-throughput kinome signatures
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