Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations.
Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations.
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DOI：
10.1038/onc.2013.418
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发表时间：
2014-09-25
期刊：
影响因子：
8
通讯作者：
Bastian BC
中科院分区：
文献类型：
--
作者：
Chen X;Wu Q;Tan L;Porter D;Jager MJ;Emery C;Bastian BC
葡萄膜黑色素瘤(UM)是一种遗传和生物学上截然不同的黑色素瘤类型，一旦转移，目前还没有有效的治疗方法。80%的UM存在GαQ家族成员GNAQ和GNA11的突变。了解这些癌蛋白下游的效应通路对于确定靶向治疗的机会很重要。我们报道由于GNAQ或GNA11突变，蛋白激酶C(PKC)和MAPK通路被一致激活。在携带GNAQ或GNA11突变的黑色素瘤细胞系中，用AEB071或AHT956抑制PKC和MAPK信号转导并选择性地诱导G1期停滞。相反，用两种不同的MEK抑制剂PD0325901和MEK162处理黑色素瘤细胞株，无论其突变状态如何，都能抑制其增殖，这表明在GNAQ或GNA11突变的背景下，MAPK的激活可以归因于激活的PKC。在转导GNAQQ209L的黑素细胞的同种异体移植模型中，AEB071显著减缓了肿瘤的生长，但不会导致肿瘤缩小。体内和体外研究表明，单独的PKC抑制剂不能诱导MAP-K信号的持续抑制。然而，联合使用PKC和MEK抑制剂，无论是PD0325901还是MEK162，都能持续抑制MAP-K通路，并在体外显示出很强的协同抑制增殖和诱导细胞凋亡的作用。此外，联合抑制PKC和MEK在体内是有效的，在葡萄膜黑色素瘤异种移植模型中导致显著的肿瘤消退。我们的数据确定PKC是具有GNAQ或GNA11突变的黑色素瘤患者的合理治疗靶点，并证明联合抑制MEK和PKC是协同的，与单独使用任何一种方法相比，疗效更好。
Uveal melanoma (UM) is a genetically and biologically distinct type of melanoma, and once metastatic there is no effective treatment currently available. 80% of UMs harbor mutations in the Gαq family members GNAQ and GNA11. Understanding the effector pathways downstream of these oncoproteins is important to identify opportunities for targeted therapy. We report consistent activation of the protein kinase C (PKC) and MAPK pathways as a consequence of GNAQ or GNA11 mutation. PKC inhibition with AEB071 or AHT956 suppressed PKC and MAPK signalling and induced G1 arrest selectively in melanoma cell lines carrying GNAQ or GNA11 mutations. In contrast, treatment with two different MEK inhibitors, PD0325901 and MEK162, inhibited the proliferation of melanoma cell lines irrespective of their mutation status, indicating that in the context of GNAQ or GNA11 mutation, MAPK activation can be attributed to activated PKC. AEB071 significantly slowed the growth of tumors in an allograft model of GNAQQ209L transduced melanocytes, but did not induce tumor shrinkage. In vivo and in vitro studies showed that PKC inhibitors alone were unable to induce sustained suppression of MAP-kinase signaling. However, combinations of PKC and MEK inhibition, using either PD0325901 or MEK162, led to sustained MAP-kinase pathway inhibition and showed a strong synergistic effect in halting proliferation and in inducing apoptosis in vitro. Furthermore, combining PKC and MEK inhibition was efficacious in vivo, causing marked tumor regression in a uveal melanoma xenograft model. Our data identifies PKC as a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations, and demonstrates combined MEK and PKC inhibition is synergistic, with superior efficacy compared to treatment with either approach alone.