摘要
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.
摘要译文
几个Eph受体酪氨酸激酶（RTK）是通常过度表达在上皮细胞和间质癌，并被认为是有希望的治疗靶标。虽然弗受体及其配体肝配蛋白之间的相互作用正常刺激激酶活性，一般是肿瘤抑制，显著弗过表达可活化配体和/或激酶依赖信号通路促进肿瘤形成。单一试剂激酶抑制剂被广泛用于靶向RTK驱动肿瘤，但获得并从头耐这种试剂是一个主要的限制，以有效的临床使用。越来越多的证据表明，EPHS可以通过针对其他RTK的“漏”或低特异性激酶抑制剂所抑制。这种脱靶效应可能因此无意中促进配体和/或激酶依赖致癌弗信令，从而提供一种新的机制，通过它的抗有RTK抑制剂可出现。我们建议，结合具体的，非渗漏激酶抑制剂与弗信令的肿瘤抑制刺激可提供用于克服治疗引起电阻和临床失败更有效的治疗选择。
A. C. Herington, I. Mertens-Walker, J. E. Lisle, M. Maharaj, and S.-A. Stephenson. Inhibiting Eph kinase activity may not be “Eph”ective for cancer treatment[J]. Growth Factors, 2014,32(6): 207-213