Numerous agents targeting various phosphatidylinositol 3-kinase (PI3K) pathway components, including PI3K, AKT and mTOR, have been tested in oncology clinical trials, resulting in regulatory approvals for the treatment of selected patients with breast cancer, certain other solid tumours or particular haematological malignancies. However, given the prominence of PI3K signalling in cancer and the crucial role of this pathway in linking cancer growth with metabolism, these clinical results could arguably be improved upon. In this Review, we discuss past and present efforts to overcome the somewhat limited clinical efficacy of PI3Kα pathway inhibitors, including optimization of inhibitor specificity, patient selection and biomarkers across cancer types, with a focus on breast cancer, as well as identification and abrogation of signalling-related and metabolic mechanisms of resistance, and interventions to improve management of prohibitive adverse events. We highlight the advantages and limitations of laboratory-based model systems used to study the PI3K pathway, and propose technologies and experimental inquiries to guide the future clinical deployment of PI3K pathway inhibitors in the treatment of cancer.

许多靶向各种磷脂酰肌醇 3-激酶 (PI3K) 通路成分（包括 PI3K、AKT 和 mTOR）的药物已经在肿瘤学临床试验中进行了测试，最终获得监管部门批准用于治疗特定的乳腺癌、某些其他实体瘤或特定血液病患者恶性肿瘤。然而，鉴于 PI3K 信号在癌症中的突出地位以及该通路在将癌症生长与新陈代谢联系起来方面的关键作用，这些临床结果可以说是可以改进的。在这篇综述中，我们讨论了过去和现在为克服 PI3Kα 通路抑制剂有限的临床疗效所做的努力，包括优化抑制剂特异性、患者选择和跨癌症类型的生物标志物，重点是乳腺癌、以及识别和消除与信号相关的耐药机制和代谢机制，以及改善禁止性不良事件管理的干预措施。我们强调了用于研究 PI3K 通路的基于实验室的模型系统的优点和局限性，并提出技术和实验调查以指导 PI3K 通路抑制剂在癌症治疗中的未来临床部署。