Inhibition of the CRAF/prohibitin interaction reverses CRAF-dependent resistance to vemurafenib
Inhibition of the CRAF/prohibitin interaction reverses CRAF-dependent resistance to vemurafenib
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DOI：
10.1038/onc.2016.214
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发表时间：
2017-01-19
期刊：
影响因子：
8
通讯作者：
Orlow, S. J.
中科院分区：
文献类型：
--
作者：
Doudican, N. A.;Orlow, S. J.
激活BRAF突变促进促分裂原活化蛋白激酶（MAPK）信号通路的组成性激活，并且在多种人类恶性肿瘤（包括黑素瘤和结肠癌）中是常见的。已经开发了几种小分子BRAF抑制剂，如维罗非尼，并显示出显著的临床疗效。然而，耐药性通常出现在大多数黑素瘤患者中。研究表明，通过CRAF过表达和失调重新激活MAPK信号传导是黑色素瘤中维罗非尼耐药的机制。抑癌蛋白（Prohibitins，PHBs）是一种高度保守的蛋白质，被认为控制细胞周期、衰老和肿瘤抑制。PHB 1通过与CRAF直接结合而对CRAF介导的ERK 1/2活化至关重要。我们开发了一种CRAF介导的黑色素瘤细胞维罗非尼耐药模型，以评估CRAF和PHB 1之间的相互作用在BRAF靶向药物耐药中的重要性。我们证明，CRAF过表达使黑色素瘤细胞对BRAF靶向药物产生耐药性。此外，用天然化合物罗格列胺A治疗破坏了黑素瘤细胞中PHB和CRAF之间的相互作用，从而减少了MEK 1/2和ERK 1/2信号传导，抑制了黑素瘤细胞生长并诱导了细胞凋亡。这些化合物的功效也在人黑素瘤异种移植模型中得到证实。总之，这些数据表明，PHB 1可能作为一种新的，药物靶点在CRAF介导的维罗非尼耐药性。
Activating BRAF mutations promote constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway and are common in a variety of human malignancies, including melanoma and colon cancer. Several small molecule BRAF inhibitors such as vemurafenib have been developed and demonstrate remarkable clinical efficacy. However, resistance typically emerges in most melanoma patients. Studies have demonstrated that reactivation of MAPK signaling via CRAF overexpression and dysregulation is a mechanism for vemurafenib resistance in melanoma. Prohibitins (PHBs) are highly conserved proteins that are thought to control the cell cycle, senescence and tumor suppression. PHB1 is essential for CRAF-mediated ERK1/2 activation through direct binding to CRAF. We developed a CRAF-mediated model of vemurafenib resistance in melanoma cells to assess the importance of the interaction between CRAF and PHB1 in resistance to BRAF-targeting agents. We demonstrate that CRAF overexpression renders melanoma cells resistant to BRAF-targeting agents. Moreover, treatment with the natural compound rocaglamide A disrupts the interaction between PHB and CRAF in melanoma cells, thus reducing MEK1/2 and ERK1/2 signaling, inhibiting melanoma cell growth and inducing apoptosis. The efficacy of these compounds was also demonstrated in a human melanoma xenograft model. Taken together, these data suggest that PHB1 may serve as a novel, druggable target in CRAF-mediated vemurafenib resistance.