Mutations in PIK3CA, which encodes the p110α subunit of the insulin-activated phosphatidylinositol-3 kinase (PI3K), and loss of function mutations in PTEN, which encodes a phosphatase that degrades the phosphoinositide lipids generated by PI3K, are among the most frequent events in human cancers1,2. However, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance to treatment. As p110α mediates virtually all cellular responses to insulin, targeted inhibition of this enzyme disrupts glucose metabolism in multiple tissues. For example, blocking insulin signalling promotes glycogen breakdown in the liver and prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in transient hyperglycaemia within a few hours of PI3K inhibition. The effect is usually transient because compensatory insulin release from the pancreas (insulin feedback) restores normal glucose homeostasis3. However, the hyperglycaemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, necessitates discontinuation of therapy3–6. We hypothesized that insulin feedback induced by PI3K inhibitors may reactivate the PI3K–mTOR signalling axis in tumours, thereby compromising treatment effectiveness7,8. Here we show, in several model tumours in mice, that systemic glucose–insulin feedback caused by targeted inhibition of this pathway is sufficient to activate PI3K signalling, even in the presence of PI3K inhibitors. This insulin feedback can be prevented using dietary or pharmaceutical approaches, which greatly enhance the efficacy/toxicity ratios of PI3K inhibitors. These findings have direct clinical implications for the multiple p110α inhibitors that are in clinical trials and provide a way to increase treatment efficacy for patients with many types of tumour.Glucose–insulin feedback can reactivate PI3K in tumours treated with PI3K inhibitors, reducing therapeutic efficacy, but this effect can be reduced by using drugs or diet to suppress the insulin response.

中文翻译：

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抑制胰岛素反馈可增强 PI3K 抑制剂的功效

PIK3CA 突变（编码胰岛素激活的磷脂酰肌醇 3 激酶 (PI3K) 的 p110α 亚基）和 PTEN（编码降解 PI3K 产生的磷酸肌醇脂质的磷酸酶）的功能丧失突变，是以下疾病中最常见的事件之一。人类癌症1,2。然而，PI3K 的药理学抑制导致了不同的临床反应，增加了对治疗产生抗性的固有机制的可能性。由于 p110α 几乎介导所有细胞对胰岛素的反应，因此对这种酶的靶向抑制会破坏多个组织中的葡萄糖代谢。例如，阻断胰岛素信号会促进肝脏中的糖原分解并阻止骨骼肌和脂肪组织中的葡萄糖摄取，从而在 PI3K 抑制的几小时内导致暂时性高血糖。这种效果通常是短暂的，因为胰腺的代偿性胰岛素释放（胰岛素反馈）恢复了正常的葡萄糖稳态3。然而，任何程度的胰岛素抵抗患者的高血糖可能会加剧或延长，在这些情况下，需要停止治疗3-6。我们假设由 PI3K 抑制剂诱导的胰岛素反馈可能会重新激活肿瘤中的 PI3K-mTOR 信号轴，从而影响治疗效果 7,8。在这里，我们表明，在小鼠的几种模型肿瘤中，即使存在 PI3K 抑制剂，由该途径的靶向抑制引起的全身葡萄糖 - 胰岛素反馈也足以激活 PI3K 信号传导。可以使用饮食或药物方法来防止这种胰岛素反馈，这大大提高了 PI3K 抑制剂的功效/毒性比。这些发现对临床试验中的多种 p110α 抑制剂具有直接的临床意义，并为提高多种类型肿瘤患者的治疗效果提供了一种方法。葡萄糖-胰岛素反馈可以重新激活用 PI3K 抑制剂治疗的肿瘤中的 PI3K，降低治疗效果，但是可以通过使用药物或饮食来抑制胰岛素反应来减少这种影响。