Combination of AKT inhibitor ARQ 092 and sorafenib potentiates inhibition of tumor progression in cirrhotic rat model of hepatocellular carcinoma.
Combination of AKT inhibitor ARQ 092 and sorafenib potentiates inhibition of tumor progression in cirrhotic rat model of hepatocellular carcinoma.
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DOI：
10.18632/oncotarget.24298
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发表时间：
2018-02-16
期刊：
影响因子：
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通讯作者：
Decaens T
中科院分区：
文献类型：
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作者：
Jilkova ZM;Kuyucu AZ;Kurma K;Ahmad Pour ST;Roth GS;Abbadessa G;Yu Y;Schwartz B;Sturm N;Marche PN;Hainaut P;Decaens T
晚期肝细胞癌（HCC）患者的预后很差。AKT通路在几乎一半的HCC病例中被激活，此外，长期暴露于HCC的常规药物治疗索拉非尼通常导致AKT过度激活，导致HCC耐药。因此，评估选择性变构AKT抑制剂ARQ 092（Miransertib）与索拉非尼联合使用的安全性和疗效非常重要。在这里，我们证明了在体外ARQ 092与索拉非尼的组合协同抑制增殖，促进凋亡，并减少迁移。为了测试该组合在体内的效果，将患有二乙基亚硝胺诱导的肝硬化和完全发展的HCC的大鼠随机化并用媒介物、索拉非尼、ARQ 092或ARQ 092与索拉非尼的组合（n=7/组）治疗6周。与对照或单药治疗相比，联合治疗显著降低了肿瘤进展、肿瘤大小和平均肿瘤数量。这种效应与凋亡反应的显著增加以及增殖和血管生成的减少相关。天狼星红染色显示肝纤维化减少。此外，治疗改善了血液和肿瘤微环境中的免疫反应。因此，ARQ 092与索拉非尼的组合增强了对肿瘤进展的抑制，并为晚期HCC患者提供了治疗改善的可能性。
The prognosis of patients with advanced hepatocellular carcinoma (HCC) is very poor. The AKT pathway is activated in almost half of HCC cases and in addition, long term exposure to conventional drug treatment of HCC, sorafenib, often results in over-activation of AKT, leading to HCC resistance. Therefore, it is important to assess the safety and the efficacy of selective allosteric AKT inhibitor ARQ 092 (Miransertib) in combination with sorafenib. Here, we demonstrated in vitro that the combination of ARQ 092 with sorafenib synergistically suppressed proliferation, promoted apoptosis, and reduced migration. To test the effect of the combination in vivo, rats with diethylnitrosamine-induced cirrhosis and fully developed HCC were randomized and treated with vehicle, sorafenib, ARQ 092 or the combination of ARQ 092 with sorafenib; (n=7/group) for 6 weeks. Tumor progression, size of tumors and the mean tumor number were significantly reduced by the combination treatment compared to the control or single treatments. This effect was associated with a significant increase in apoptotic response and reduction in proliferation and angiogenesis. Sirius red staining showed a decrease in liver fibrosis. Moreover, treatments improved immune response in blood and in tumor microenvironment. Thus, the combination of ARQ 092 with sorafenib potentiates inhibition of tumor progression and gives the possibility of therapeutic improvement for patients with advanced HCC.