a The Pennsylvania State University College of Medicine , Department of Pharmacology , Hershey , PA.
f The Pennsylvania State University College of Medicine , The Melanoma and Skin Cancer Center , Hershey , PA.
Cancer Biol Ther. 2018 Jan 2;19(1):53-62. doi: 10.1080/15384047.2017.1360446. Epub 2017 Nov 30.
AKT3 is one of the major therapeutic targets in melanoma but clinically targeting AKT3 alone seems to be an ineffective therapeutic approach. To identify unique strategies to enhance the efficacy of targeting AKT3, a screen was undertaken where AKT3 was co-targeted with a panel of kinases important in melanoma development. The screen identified WEE1 as the most potent target that when inhibited along with AKT3 would enhance the efficacy of targeting AKT3 in melanoma. RNAi mediated inhibition of AKT3 and WEE1 synergistically inhibited the viability of melanoma cells leading to a 65-75% decrease in tumor development. This approach was effective by mechanistically modulating pathways associated with the transcription factors p53 and FOXM1. Simultaneously regulating the activity of these two transcriptionally driven pathways, cooperatively deregulated cell cycle control and DNA damage repair to synergistically kill melanoma cells. This study uniquely identifies a potential approach to improve the efficacy of targeting AKT3 in melanoma.
AKT3 是黑色素瘤的主要治疗靶点之一，但单独针对 AKT3 的临床治疗似乎是一种无效的治疗方法。为了确定增强 AKT3 靶向治疗效果的独特策略，进行了一项筛选，其中 AKT3 与黑色素瘤发展中重要的激酶进行了联合靶向治疗。筛选确定 WEE1 是最有效的靶点，当与 AKT3 一起抑制时，可增强 AKT3 在黑色素瘤中的靶向治疗效果。AKT3 和 WEE1 的 RNAi 介导抑制协同抑制黑色素瘤细胞的活力，导致肿瘤发展减少 65-75%。这种方法通过机械调节与转录因子 p53 和 FOXM1 相关的途径有效，同时调节这两个转录驱动途径的活性，协同调节细胞周期控制和 DNA 损伤修复，从而协同杀死黑色素瘤细胞。这项研究独特地确定了一种提高 AKT3 靶向治疗黑色素瘤效果的潜在方法。
