Ligand-independent EPHA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype.
Ligand-independent EPHA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype.
复制标题
不依赖配体的EPHA2信号传导驱动靶向治疗介导的转移性黑色素瘤表型的采用。
DOI：
10.1158/2159-8290.cd-14-0293
复制
发表时间：
2015-03
期刊：
影响因子：
28.2
通讯作者：
Smalley KS
中科院分区：
文献类型：
--
作者：
Paraiso KH;Das Thakur M;Fang B;Koomen JM;Fedorenko IV;John JK;Tsao H;Flaherty KT;Sondak VK;Messina JL;Pasquale EB;Villagra A;Rao UN;Kirkwood JM;Meier F;Sloot S;Gibney GT;Stuart D;Tawbi H;Smalley KS
许多BRAF抑制剂耐药的患者可以在新的部位发生疾病，这表明药物诱导的选择压力驱动了转移。在这里，我们使用基于质谱的磷酸化蛋白质组学筛选来揭示配体无关的EphA2信号作为对BRAF抑制剂治疗的适应，导致采用转移表型。epha2介导的侵袭是AKT依赖性的，并且在去除药物以及通过PI3K和AKT抑制后很容易逆转。在异种移植瘤模型中，BRAF抑制导致EphA2阳性转移的发展。一项对BRAF抑制剂治疗的黑色素瘤患者的回顾性分析显示，68%治疗失败的患者在新的疾病部位发生转移，而达卡巴嗪治疗的患者为35%。接受BRAF抑制剂治疗的患者的黑色素瘤标本以及治疗失败的患者的转移性标本的进一步免疫组化染色显示EphA2染色增加。我们认为，抑制与配体无关的EphA2信号可能会限制与BRAF抑制剂治疗相关的转移。
Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here we used mass spectrometry-based phosphoproteomic screening to uncover ligand-independent EphA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EphA2-mediated invasion was AKT-dependent and readily reversible upon removal of drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EphA2 positive metastases. A retrospective analysis of melanoma patients on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared to 35% in patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EphA2 staining. We suggest that inhibition of ligand-independent EphA2 signaling may limit metastases associated with BRAF inhibitor therapy.