EPHA2 Is a Mediator of Vemurafenib Resistance and a Novel Therapeutic Target in Melanoma

摘要: BRAF(V600E) is the most common oncogenic lesion in melanoma and results constitutive activation of mitogen-activated protein kinase (MAPK) pathway uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize signaling, restrain cellular growth improve patient outcome. Although several mechanisms resistance described, directed solutions overcome these lesions are still lacking. Herein, we found that can be (i) mediated by EphA2- a member largest receptor tyrosine kinases (RTK) subfamily erythropoietin-producing hepatocellular (Eph) receptors (ii) associated with greater phenotypic dependence on EphA2. Furthermore, developed series first-in-class EphA2 show new compounds potently induce apoptosis, suppress viability abrogate tumorigenic cells, including those resistant vemurafenib. These provide proof-of-concept RTK-guided growth, therapeutic resistance, prospectively defined selectively targeted.