Chen Jinghong, Yin Rutie
Department of Obstetrics and Gynecology, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, Sichuan, China.
Front Oncol. 2025 Jul 17;15:1547083. doi: 10.3389/fonc.2025.1547083. eCollection 2025.
The PI3K/AKT/mTOR pathway serves as a critical signaling nexus in cancer, with AKT acting as a central regulator of tumor cell proliferation, survival, metabolism, and therapy resistance. AKT inhibitors show promising but variable anti-tumor activity in preclinical and clinical studies. Currently, multiple classes of AKT inhibitors-PH domain competitors (perifosine), allosteric inhibitors (MK-2206), and ATP-competitive agents (AZD5363, GSK2110183, GSK2141795, and GDC-0068) are under development, with several agents in phase II/III trials. While early results demonstrated encouraging response rates and prolonged PFS in selected patients, significant challenges remain. The efficacy needs confirmation in larger trials, toxicities require better management, and resistance mechanisms demand further elucidation to guide optimal therapeutic strategies. This study systematically reviews recent AKTi research in gynecological cancers, aiming to provide a theoretical foundation for identifying potential biomarkers, overcoming drug resistance, and developing prognostic models. These insights may further facilitate the clinical translation of key therapeutic agents.
PI3K/AKT/mTOR信号通路是癌症中的关键信号枢纽，AKT作为肿瘤细胞增殖、存活、代谢及治疗耐药性的核心调节因子。在临床前和临床研究中，AKT抑制剂显示出有前景但不尽相同的抗肿瘤活性。目前，多种类型的AKT抑制剂——PH结构域竞争剂（哌立福新）、变构抑制剂（MK-2206）以及ATP竞争性药物（AZD5363、GSK2110183、GSK2141795和GDC-0068）正在研发中，有几种药物已进入II/III期试验。虽然早期结果显示在部分患者中缓解率令人鼓舞且无进展生存期延长，但仍存在重大挑战。疗效需要在更大规模试验中得到证实，毒性需要更好地管理，耐药机制需要进一步阐明以指导最佳治疗策略。本研究系统回顾了妇科癌症中近期AKT抑制剂的研究，旨在为识别潜在生物标志物、克服耐药性及开发预后模型提供理论基础。这些见解可能进一步促进关键治疗药物的临床转化。
