Le Grand Marion, Kimpton Kathleen, Gana Christine C, Valli Emanuele, Fletcher Jamie I, Kavallaris Maria
Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, New South Wales 2052, Australia.
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW, Sydney, New South Wales 2052, Australia.
ACS Pharmacol Transl Sci. 2020 Jan 23;3(1):148-160. doi: 10.1021/acsptsci.9b00085. eCollection 2020 Feb 14.
-amplified neuroblastoma is one of the deadliest forms of childhood cancer and remains a significant clinical challenge. Direct pharmacological inhibition of MYCN is not currently achievable. One strategy could be to target the AKT/GSK3β pathway, which directly regulates the stability of the MYCN protein. Numerous potent and isoform-specific small-molecule AKT inhibitors have been developed. However, the selection of the right drug combinations in the relevant indication will have a significant impact on AKT inhibitor clinical success. To maximally exploit the potential of AKT inhibitors, a better understanding of AKT isoform functions in cancer is crucial. Here using RNAi to downregulate specific AKT isoforms, we demonstrated that loss of total AKT activity rather than isoform-specific expression was necessary to decrease MYCN expression and cause a significant decrease in neuroblastoma cell proliferation. Consistent with these observations, isoform-specific pharmacological inhibition of AKT was substantially less effective than pan-AKT inhibition in combination with cytotoxic drugs in -amplified neuroblastoma. The allosteric pan-AKT inhibitor perifosine had promising and activity in combination with conventional cytotoxic drugs in -amplified neuroblastoma cells. Our results demonstrated that perifosine drug combination was able to induce apoptosis and downregulate ABC transporter expression. Collectively, this study shows that selecting pan-AKT inhibitors rather than isoform-specific drugs to synergize with first-line chemotherapy treatment should be considered for clinical trials for aggressive neuroblastoma and, potentially, other MYCN -driven cancers.
MYCN 扩增的神经母细胞瘤是儿童癌症中最致命的形式之一，仍然是一个重大的临床挑战。目前无法直接通过药物抑制 MYCN。一种策略可能是靶向 AKT/GSK3β 信号通路，该通路直接调节 MYCN 蛋白的稳定性。已经开发出许多强效且具有亚型特异性的小分子 AKT 抑制剂。然而，在相关适应症中选择正确的药物组合将对 AKT 抑制剂的临床成功产生重大影响。为了最大程度地发挥 AKT 抑制剂的潜力，更好地了解 AKT 亚型在癌症中的功能至关重要。在这里，我们使用 RNAi 下调特定的 AKT 亚型，证明降低 MYCN 表达并导致神经母细胞瘤细胞增殖显著减少需要的是总 AKT 活性的丧失而非亚型特异性表达的丧失。与这些观察结果一致，在 MYCN 扩增的神经母细胞瘤中，AKT 亚型特异性的药理抑制作用远不如泛 AKT 抑制作用与细胞毒性药物联合有效。变构泛 AKT 抑制剂哌立福新与传统细胞毒性药物联合使用时，在 MYCN 扩增的神经母细胞瘤细胞中具有良好的活性。我们的结果表明，哌立福新药物组合能够诱导细胞凋亡并下调 ABC 转运蛋白的表达。总体而言，本研究表明，对于侵袭性神经母细胞瘤以及可能的其他由 MYCN 驱动的癌症的临床试验，应考虑选择泛 AKT 抑制剂而非亚型特异性药物与一线化疗联合使用。
