Dataset Information

Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway Analysis in Lung Cancer.

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.

SUBMITTER: Ferguson BD

PROVIDER: S-EPMC4466581 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway Analysis in Lung Cancer.

Ferguson Benjamin D BD Carol Tan Yi-Hung YH Kanteti Rajani S RS Liu Ren R Gayed Matthew J MJ Vokes Everett E EE Ferguson Mark K MK John Iafrate A A Gill Parkash S PS Salgia Ravi R

Scientific reports 20150615

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. ...[more]

PMID: 26073592

Similar Datasets

Project description:BackgroundThe Mesenchymal epithelial transition factor (MET) gene encodes a receptor tyrosine kinase with pleiotropic functions in cancer. MET exon 14 skipping alterations and high-level MET amplification are oncogenic and targetable genetic changes in patients with non-small-cell lung cancer (NSCLC). Resistance to tyrosine kinase inhibitors (TKIs) has been a major challenge for targeted therapies that impairs their clinical efficacies.MethodsEighty-six NSCLC patients were categorized into three cohorts based on the time of detecting MET tyrosine kinase domain (TKD) mutations (cohort 1: at baseline; cohort 2: after MET-TKI treatment; cohort 3: after EGFR-TKI treatment). Baseline and paired TKI treatment samples were analyzed by targeted next-generation sequencing.ResultsMET TKD mutations were highly prevalent in METex14-positive NSCLC patients after MET-TKI treatment, including L1195V, D1228N/H/Y/E, Y1230C/H/N/S, and a double-mutant within codons D1228 and M1229. Missense mutations in MET TKD were also identified at baseline and in post-EGFR-TKI treatment samples, which showed different distribution patterns than those in post-MET-TKI treatment samples. Remarkably, H1094Y and L1195F, absent from MET-TKI-treated patients, were the predominant type of MET TKD mutations in patients after EGFR-TKI treatment. D1228H, which was not found in treatment-naïve patients, also accounted for 14.3% of all MET TKD mutations in EGFR-TKI-treated samples. Two patients with baseline EGFR-sensitizing mutations who acquired MET-V1092I or MET-H1094Y after first-line EGFR-TKI treatment experienced an overall improvement in their clinical symptoms, followed by targeted therapy with MET-TKIs.ConclusionsMET TKD mutations were identified in both baseline and patients treated with TKIs. MET-H1094Y might play an oncogenic role in NSCLC and may confer acquired resistance to EGFR-TKIs. Preliminary data indicates that EGFR-mutated NSCLC patients who acquired MET-V1092I or MET-H1094Y may benefit from combinatorial therapy with EGFR-TKI and MET-TKI, providing insights into personalized medical treatment.

Dataset Information

Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway Analysis in Lung Cancer.

Publications

Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway Analysis in Lung Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets