Department of Visceral Surgery, Lausanne University Hospital, University of Lausanne, Pavillon 4, Av de Beaumont, 1011, Lausanne, Switzerland.
Biochem Biophys Res Commun. 2019 Jun 4;513(3):546-552. doi: 10.1016/j.bbrc.2019.04.044. Epub 2019 Apr 10.
Whilst effects of anti-cancer drugs have been thoroughly explored, little is known about the repercussion of drug cessation. However, this has important clinical relevance since several clinical protocols such as intermittent drug scheduling lead to frequent drug discontinuation. In this study, we have thus investigated the consequences of withdrawal of agents that target the PI3K/AKT/mTOR signaling pathway in cancer cells. We report that washout of kinase inhibitors of mTOR or PI3K inhibitors led to a rapid and sustainable overactivation of AKT. Consequently, proliferation of tumor cells was significantly higher following drug washout in cancer cells that were pre-treated with mTOR or PI3K inhibitors compared to untreated cells. This effect was prevented by the addition of an AKT inhibitor following drug washout. Rebound AKT overactivation induced by mTOR or PI3K inhibitors discontinuation was mediated by IGF-1R, as demonstrated by its prevention in the presence of an IGF-1R inhibitor and by increased IGF-1R phosphorylation in treated cells versus control cells. Taken together, our results show that discontinuation of PI3K or mTOR inhibitors results in AKT overactivation that promotes tumor growth. They further highlight the benefit of adding an AKT inhibitor following cessation of PI3K or mTOR inhibitors.
虽然抗癌药物的作用已经得到了深入的研究，但药物停止使用的影响却知之甚少。然而，这具有重要的临床意义，因为一些临床方案，如间歇性药物给药，会导致药物频繁停药。在这项研究中，我们研究了针对 PI3K/AKT/mTOR 信号通路的药物在癌细胞中停药的后果。我们报告说，mTOR 激酶抑制剂或 PI3K 抑制剂的洗脱会导致 AKT 的快速和持续过度激活。因此，与未处理的细胞相比，在用 mTOR 或 PI3K 抑制剂预处理的癌细胞中，药物洗脱后细胞的增殖明显更高。在用药物洗脱后添加 AKT 抑制剂可以防止这种效应。正如 IGF-1R 抑制剂存在时所证明的那样，mTOR 或 PI3K 抑制剂停药引起的 AKT 过度激活是由 IGF-1R 介导的，并且在处理过的细胞中 IGF-1R 磷酸化增加。综上所述，我们的结果表明，PI3K 或 mTOR 抑制剂的停药会导致 AKT 过度激活，从而促进肿瘤生长。它们进一步强调了在停止使用 PI3K 或 mTOR 抑制剂后添加 AKT 抑制剂的益处。
