Aberrant activation of the PI3K-AKT pathway is common in many cancers including melanoma, and AKT1, 2 and 3 (AKT1-3) are bona fide oncoprotein kinases with well-validated downstream effectors. However, efforts to pharmacologically inhibit AKT have proven to be largely ineffective. In this study, we observed paradoxical effects following either pharmacologic or genetic inhibition of AKT1-3 in melanoma cells. Although pharmacological inhibition was without effect, genetic silencing of all three AKT paralogs significantly induced melanoma cell death through effects on mTOR. This phenotype was rescued by exogenous AKT1 expression in a kinase dependent manner. Pharmacological inhibition of PI3K and mTOR with a novel dual inhibitor effectively suppressed melanoma cell proliferation in vitro and inhibited tumor growth in vivo. Furthermore, this single agent targeted therapy was well tolerated in vivo and was effective against MAPK inhibitor resistant patient-derived melanoma xenografts. These results suggest that inhibition of PI3K and mTOR with this novel dual inhibitor may represent a promising therapeutic strategy in this disease in both the first line and MAPK inhibitor resistant setting.

中文翻译：

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AKT 基因沉默通过 mTOR 抑制诱导黑色素瘤细胞死亡

PI3K-AKT 通路的异常激活在包括黑色素瘤在内的许多癌症中很常见，AKT1、2 和 3 (AKT1-3) 是真正的癌蛋白激酶，具有经过充分验证的下游效应器。然而，药物抑制 AKT 的努力已被证明基本上无效。在这项研究中，我们观察到黑色素瘤细胞中 AKT1-3 的药物或基因抑制后产生的矛盾效应。尽管药物抑制没有效果，但所有三种 AKT 旁系同源物的基因沉默通过对 mTOR 的影响显着诱导黑色素瘤细胞死亡。这种表型可以通过外源 AKT1 以激酶依赖性方式表达来挽救。使用新型双重抑制剂对 PI3K 和 mTOR 进行药理学抑制，可有效抑制体外黑色素瘤细胞增殖，并抑制体内肿瘤生长。此外，这种单药靶向治疗在体内具有良好的耐受性，并且对 MAPK 抑制剂耐药的患者来源的黑色素瘤异种移植物有效。这些结果表明，用这种新型双重抑制剂抑制 PI3K 和 mTOR 可能代表了一线和 MAPK 抑制剂耐药环境中该疾病的一种有前景的治疗策略。