title: Inhibiting Eph kinase activity may not be "Eph"ective for cancer treatment.
abstract: Several Eph receptor tyrosine kinases (RTKs) are commonly over-expressed in epithelial and mesenchymal cancers and are recognized as promising therapeutic targets. Although normal interaction between Eph receptors and their ephrin ligands stimulates kinase activity and is generally tumor suppressive, significant Eph over-expression allows activation of ligand- and/or kinase-independent signaling pathways that promote oncogenesis. Single-agent kinase inhibitors are widely used to target RTK-driven tumors but acquired and de novo resistance to such agents is a major limitation to effective clinical use. Accumulating evidence suggests that Ephs can be inhibited by "leaky" or low-specificity kinase inhibitors targeted at other RTKs. Such off-target effects may therefore inadvertently promote ligand- and/or kinase-independent oncogenic Eph signaling, thereby providing a new mechanism by which resistance to the RTK inhibitors can emerge. We propose that combining specific, non-leaky kinase inhibitors with tumor-suppressive stimulators of Eph signaling may provide more effective treatment options for overcoming treatment-induced resistance and clinical failure.
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology , Queensland , Australia and.
authors.forename: A C
authors.initials: AC
authors.lastname: Herington
authors.forename: I
authors.initials: I
authors.lastname: Mertens-Walker
authors.forename: J E
authors.initials: JE
authors.lastname: Lisle
authors.forename: M
authors.initials: M
authors.lastname: Maharaj
authors.forename: S-A
authors.initials: SA
authors.lastname: Stephenson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D036081:Receptors, Eph Family / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D036081:Receptors, Eph Family
keywords: Cancer resistance; Eph receptors; kinase inhibitors