College of Life Science, Yangtze University, Jingzhou, China.
College of Physical Education and Health, Chongqing College of International Business and Economics, Chongqing, China.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2237209. doi: 10.1080/14756366.2023.2237209.
Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.
磷酸肌醇 3-激酶 (PI3K) 和磷酸肌醇 3-激酶相关蛋白激酶 (PIKK) 是两种结构相关的激酶家族，在细胞生长和 DNA 损伤修复中发挥着重要作用。PIKK 成员功能障碍和 PI3K/AKT/mTOR 信号通路的异常刺激与包括癌症在内的多种疾病有关。在过去的几十年中，与 PI3K/AKT/mTOR 信号相关的许多抑制剂在癌症治疗方面取得了重大进展，如 copanlisib 和 sirolimus。值得注意的是，大多数与 DNA 损伤反应相关的 PIKK 抑制剂（如 VX-970 和 M3814）在临床试验中也显示出良好的疗效。然而，这些药物仍需要合适的联合治疗来克服耐药性或提高抗肿瘤活性。基于上述事实，我们总结了 PIKK、PI3K 和 AKT 抑制剂在人类恶性肿瘤治疗中的疗效以及靶向治疗的耐药机制，以期为癌症治疗提供更深入的见解。
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