The PI3K/Akt/mTOR signalling network is activated in almost 90% of all glioblastoma, the most common primary brain tumour, which is almost invariably lethal within 15 months of diagnosis. Despite intensive research, modulation of this signalling cascade has so far yielded little therapeutic benefit, suggesting that the role of the PI3K network as a pro-survival factor in glioblastoma and therefore a potential target in combination therapy should be re-evaluated. Therefore, we used two distinct pharmacological inhibitors that block signalling at different points of the cascade, namely, GDC-0941 (Pictilisib), a direct inhibitor of the near apical PI3K, and Rapamycin which blocks the side arm of the network that is regulated by mTOR complex 1. While both substances, at concentrations where they inhibit their primary target, have similar effects on proliferation and sensitisation for temozolomide-induced apoptosis, GDC-0941 appears to have a stronger effect on cellular motility than Rapamycin. In vivo GDC-0941 effectively retards growth of orthotopic transplanted human tumours in murine brains and significantly prolongs mouse survival. However, when looking at genetically identical cell populations that are in alternative states of differentiation, i.e. stem cell-like cells and their differentiated progeny, a more complex picture regarding the PI3K/Akt/mTOR pathway emerges. The pathway is differently regulated in the alternative cell populations and, while it contributes to the increased chemo-resistance of stem cell-like cells compared to differentiated cells, it only contributes to the motility of the latter. Our findings are the first to suggest that within a glioblastoma tumour the PI3K network can have distinct, cell-specific functions. These have to be carefully considered when incorporating inhibition of PI3K-mediated signals into complex combination therapies.

中文翻译：

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PI3K介导的信号传导对胶质母细胞瘤细胞行为的影响。

PI3K / Akt / mTOR信号网络在所有胶质母细胞瘤（最常见的原发性脑肿瘤）中几乎有90％被激活，在诊断后的15个月内几乎总是致死。尽管进行了深入研究，但迄今为止，对该信号级联的调节几乎没有产生任何治疗益处，这表明PI3K网络作为胶质母细胞瘤中生存因子的作用，因此应重新评估联合治疗中的潜在靶标。因此，我们使用了两种不同的药理学抑制剂来阻断级联反应中不同点的信号传导，分别是GDC-0941（Pictilisib）（一种近端PI3K的直接抑制剂）和雷帕霉素（Rapamycin），后者可以阻断由该药调控的网络侧臂。 mTOR复合物1.虽然两种物质都在抑制其主要目标的浓度下，对替莫唑胺诱导的细胞凋亡的增生和敏化具有相似的作用，GDC-0941似乎比雷帕霉素对细胞运动的影响更强。体内GDC-0941有效地抑制了鼠脑中原位移植的人类肿瘤的生长，并显着延长了小鼠的生存期。然而，当观察处于分化的替代状态的遗传上相同的细胞群时，即干细胞样细胞及其分化的后代，出现了关于PI3K / Akt / mTOR途径的更复杂的图景。该途径在其他细胞群中受到不同的调节，尽管与分化的细胞相比，它有助于干细胞样细胞的化学抗性增强，但仅有助于后者的运动性。我们的发现首次表明，在胶质母细胞瘤肿瘤中，PI3K网络可以具有独特的细胞特异性功能。将PI3K介导的信号抑制作用纳入复杂的联合疗法中时，必须仔细考虑这些因素。