Phosphoinositide 3-kinases (PI3Ks) play a central role in tumourigenesis with recurrent activating mutations of its p110α subunit (PIK3CA) identified in several tumours. Although several PI3K inhibitors are approved for haematological malignancies, only alpelisib was approved in solid tumours and for the treatment of PIK3CA-related overgrowth spectrum (PROS) syndrome. Traditional PI3K inhibitors inhibit both wild-type and mutant PI3K with almost equal potency, thus limiting their efficacy due to on-target toxicity. Since the initiation of phase I clinical trials investigating next generation allosteric mutant and isoform selective PIK3CA inhibitors, there has been a surge in interest in PIK3CA targeting in solid tumours. Preclinical characterisation of these compounds showed that maximal mutant protein inhibition fails to elicit metabolic and glucose homoeostasis dysregulation, one of the dose limiting toxicities of both selective and pan PI3K inhibitors. While extreme selectivity can be hypothesised to grant activity and safety advantage to these novel agents, on the other hand reduced benefit can be speculated for patients harbouring multiple or rare PIK3CA mutations. This review summarises the current understanding of PI3K alterations and the state-of-the-art treatment strategies in PI3K driven solid tumours, while also exploring the potential intrinsic and acquired resistance mechanisms to these agents, and the emerging role of mutant selective PIK3CA inhibitors.

磷酸肌醇 3-激酶 (PI3K) 在肿瘤发生中发挥核心作用，在多种肿瘤中发现其 p110α 亚基 ( PIK3CA ) 反复激活突变。尽管多种 PI3K 抑制剂被批准用于血液恶性肿瘤，但只有 alpelisib 被批准用于实体瘤和PIK3CA相关过度生长谱 (PROS) 综合征的治疗。传统的 PI3K 抑制剂以几乎相同的效力抑制野生型和突变型 PI3K，因此由于靶向毒性而限制了其功效。自从研究下一代变构突变体和异构体选择性PIK3CA抑制剂的 I 期临床试验启动以来，人们对实体瘤靶向PIK3CA的兴趣激增。这些化合物的临床前表征表明，最大突变蛋白抑制不能引起代谢和葡萄糖稳态失调，这是选择性和泛 PI3K 抑制剂的剂量限制毒性之一。虽然可以假设极端选择性可以赋予这些新药活性和安全性优势，但另一方面，可以推测携带多种或罕见 PIK3CA 突变的患者获益会减少。本综述总结了目前对 PI3K 改变的理解和 PI3K 驱动的实体瘤的最先进的治疗策略，同时还探讨了这些药物的潜在内在和获得性耐药机制，以及突变选择性PIK3CA抑制剂的新兴作用。