EPHA2 is a mediator of vemurafenib resistance and a novel therapeutic target in melanoma.
EPHA2 is a mediator of vemurafenib resistance and a novel therapeutic target in melanoma.
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Epha2是vemurafenib耐药性和黑色素瘤中新型治疗靶标的介体。
DOI：
10.1158/2159-8290.cd-14-0295
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发表时间：
2015-03
期刊：
影响因子：
28.2
通讯作者：
Tsao H
中科院分区：
文献类型：
--
作者：
Miao B;Ji Z;Tan L;Taylor M;Zhang J;Choi HG;Frederick DT;Kumar R;Wargo JA;Flaherty KT;Gray NS;Tsao H
BRAF（V600 E）是黑色素瘤中最常见的致癌病变，并导致丝裂原活化蛋白激酶（MAPK）通路的组成性激活和不受控制的细胞生长。选择性BRAF抑制剂如维罗非尼已被证明可以中和致癌信号传导，抑制细胞生长并改善患者预后。尽管已经描述了维罗非尼耐药的几种机制，但仍然缺乏克服这些耐药病变的定向解决方案。在本文中，我们发现维罗非尼抗性可以（i）由EphA2介导，EphA2是最大的受体酪氨酸激酶（RTK）亚家族产红细胞生成素肝细胞（Eph）受体的成员，和（ii）与对EphA2的更大表型依赖性相关。此外，我们开发了一系列一流的EphA2抑制剂，并表明这些新化合物有效地诱导细胞凋亡，抑制生存力并消除黑色素瘤细胞的致瘤性生长，包括那些对维罗非尼耐药的细胞。这些结果提供了概念验证，即RTK引导的生长和治疗抗性可以前瞻性地定义和选择性地靶向。
BRAF(V600E) is the most common oncogenic lesion in melanoma and results in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize oncogenic signaling, restrain cellular growth and improve patient outcome. Although several mechanisms of vemurafenib resistance have been described, directed solutions to overcome these resistance lesions are still lacking. Herein, we found that vemurafenib resistance can be (i) mediated by EphA2- a member of the largest receptor tyrosine kinases (RTK) subfamily erythropoietin-producing hepatocellular (Eph) receptors and (ii) associated with a greater phenotypic dependence on EphA2. Furthermore, we developed a series of first-in-class EphA2 inhibitors and show that these new compounds potently induce apoptosis, suppress viability and abrogate tumorigenic growth of melanoma cells, including those that are resistant to vemurafenib. These results provide proof-of-concept that RTK-guided growth, and therapeutic resistance, can be prospectively defined and selectively targeted.