Critical role for the receptor tyrosine kinase EPHB4 in esophageal cancers
Menée sur des lignées cellulaires, des échantillons tumoraux et à l'aide d'un modèle murin, cette étude suggère que l'expression du gène EPHB4 pourrait servir de biomarqueur prédictif de la réponse à une thérapie ciblée dans les cancers de l'œsophage
Esophageal cancer incidence is rising and has few treatment options. In studying receptor tyrosine kinases associated with esophageal cancers, we have identified EPHB4 to be robustly over expressed in cell lines and primary tumor tissues. In total, 94 squamous cell carcinoma (SCC), 82 adenocarcinoma, 25 dysplasia, 13 Barrett's esophagus and 25 adjacent or unrelated normal esophageal tissues were evaluated by IHC. EPHB4 expression was significantly higher in all the different histologic categories compared to adjacent normal tissues. In 13 esophageal cancer cell lines, three of the nine SCC cell lines and one of the four adenocarcinomas expressed very high levels of EPHB4. An increased gene copy number ranging from 4-20 copies was identified in a subset of the overexpressing patient samples and cell lines. We have developed a novel 4-NQO induced mouse model of esophageal cancer that recapitulates the EPHB4 expression in humans. A specific small molecule inhibitorof EPHB4 decreased cell viability in a time and dose dependent manner in three of the four cell lines tested. The small molecule inhibitor and an EPHB4 siRNA also decreased cell migration (12-40% closure in treated vs. 60-80% in untreated), with decreased phosphorylation of various tyrosyl containing proteins, EphB4 and its downstream target p125FAK. Finally, in a xenograft tumor model, an EPHB4 inhibitor abrogated tumor growth by approximately 60% compared to untreated control. EphB4 is robustly expressed and potentially serves as a novel biomarker for targeted therapy in esophageal cancers.
Cancer Research , résumé, 2012