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中华乳腺病杂志(电子版) ›› 2025, Vol. 19 ›› Issue (01) : 12 -19. doi: 10.3877/cma.j.issn.1674-0807.2025.01.003

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PI3K/AKT/mTOR 信号通路及其靶向治疗在乳腺癌中的应用
徐航程1, 王佳玉1,()   
  1. 1.100021 北京,国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院内科
  • 收稿日期:2024-10-29 出版日期:2025-02-01
  • 通信作者: 王佳玉

The PI3K/AKT/mTOR signaling pathway and its targeted therapy in breast cancer

Hangcheng Xu1, Jiayu Wang1,()   

  1. 1.Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
  • Received:2024-10-29 Published:2025-02-01
  • Corresponding author: Jiayu Wang
引用本文:

徐航程, 王佳玉. PI3K/AKT/mTOR 信号通路及其靶向治疗在乳腺癌中的应用[J/OL]. 中华乳腺病杂志(电子版), 2025, 19(01): 12-19.

Hangcheng Xu, Jiayu Wang. The PI3K/AKT/mTOR signaling pathway and its targeted therapy in breast cancer[J/OL]. Chinese Journal of Breast Disease(Electronic Edition), 2025, 19(01): 12-19.

磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(AKT)/哺乳动物雷帕霉素靶蛋白(mTOR)信号通路,简称PAM 信号通路,可通过多种机制影响乳腺癌的发生、发展,并在多种治疗手段耐药中发挥关键作用。 PAM 信号通路异常的乳腺癌患者预后通常较正常者更差。 近年来,针对PAM 信号通路的靶向治疗药物,包括PI3K 抑制剂、AKT 抑制剂、mTOR 抑制剂和PI3K/mTOR 双靶点抑制剂等,在乳腺癌的治疗中取得了较大进展,显著改善了激素受体阳性/HER-2 阴性晚期乳腺癌患者的预后。 本文系统总结了PAM 信号通路抑制剂在不同分子分型乳腺癌中的主要临床研究, 探讨了PAM 信号通路的检测及靶向药物安全性管理的挑战,预测了未来的研究方向。 通过精准检测PAM 信号通路和合理应用相关抑制剂,临床医师可以为乳腺癌患者提供更为优化的治疗方案。

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, also known as the PAM signaling pathway, influences breast cancer development and progression through various mechanisms and plays a critical role in therapeutic resistance.Breast cancer patients with aberrant PAM signaling pathway activation typically have worse prognosis compared with those with normal signaling. In recent years, targeted therapies focusing on the PAM signaling pathway,including PI3K inhibitors, AKT inhibitors, mTOR inhibitors and dual PI3K/mTOR inhibitors, have achieved significant progress in breast cancer treatment, particularly in improving the prognosis of hormone receptorpositive, HER-2-negative advanced breast cancer patients. This review systematically summarized key clinical studies on PAM signaling pathway inhibitors across different molecular subtypes of breast cancer, discussed the challenges in PAM pathway detection and safety management of targeted therapy, and predicted future directions in this field. Through precise detection of PAM signaling pathway and rational application of related inhibitors, more optimized treatment strategies for breast cancer patients are expected.

表1 PAM 信号通路抑制剂治疗晚期乳腺癌的临床研究列表
研究药物 研究人群 研究名称/阶段 例数 治疗方案 中位PFS(月) PFS风险比(95%CI 中位OS(月) OS风险比(95%CI
以PI3K为靶点
Alpelisib AI治疗失败的绝经后HR+/HER-2-晚期乳腺癌 SOLAR-1[54,29]/3期 572 氟维司群+Alpelisib 11a 0.65(0.50~0.85) 39.3a 0.86(0.64~1.15)
氟维司群+安慰剂 5.7a 31.4a
CDK4/6抑制剂经治伴有PIK3CA突变的HR+/HER-2-晚期乳腺癌 BYLieve[55]/2期 127(队列A) 氟维司群+Alpelisib 8.0 - 27.3 -
126(队列B) 来曲唑+Alpelisib 5.6 - 29.0 -
Inavolisib 有PIK3CA 突变的初治HR+/ HER-2-晚期乳腺癌 INAVO-120[34] /3 期 325 哌柏西利+氟维司群+Inavolisib 15.0 0.43(0.32~0.59) 未达到 0.64(0.43~0.97)
哌柏西利+氟维司群+安慰剂 7.3 31.3
以AKT为靶点
Capivasertib AI 治疗失败的绝经后HR+/ HER-2-晚期乳腺癌 CAPItello-291[35] /3 期 708 氟维司群+Capivasertib 7.2b 0.60 (0.51~0.71) 未达到 0.74 (0.56~0.98)
氟维司群+安慰剂 3.6b 未达到
氟维司群+Capivasertib 7.3c 0.50 (0.38~0.65) 未达到 0.69 (0.45~1.05)
氟维司群+安慰剂 3.1c 未达到
AI 治疗失败的绝经后HR+/ HER-2-晚期乳腺癌 FAKTION[56] /2 期 140 氟维司群+Capivasertib 10.3b 0.56 (0.38~0.81) 29.3b 0.66 (0.45~0.97)
氟维司群+安慰剂 4.8b 23.4b
氟维司群+Capivasertib 12.8c 0.44 (0.26~0.72) 38.9c 0.46 (0.27~0.79)
氟维司群+安慰剂 4.6c 20.0c
初治晚期TNBC PAKT[57] /2 期 140 紫杉醇+Capivasertib 5.9b 0.74(0.50~1.08) 19.1b 0.61(0.37~0.99)
紫杉醇+安慰剂 4.2b 12.6b
紫杉醇+Capivasertib 9.3c 0.30 (0.11~0.79) 未达到 0.37 (0.12~1.12)
紫杉醇+安慰剂 3.7c 10.4c
Ipatasertib 初治晚期TNBC LOTUS[58] /2 期 124 紫杉醇+Ipatasertib 6.2b 0.60 (0.37~0.98) 25.8b 0.80 (0.50~1.28)
紫杉醇+安慰剂 4.9b 16.9b
紫杉醇+Ipatasertib 9.0c 0.44 (0.20~0.99) 25.8c 1.13 (0.52~2.47)
紫杉醇+安慰剂 4.9c 22.1c
PIK3CA/ AKT1/ PTEN改变的初治晚期TNBC IPATunity130[59] /3 期 255 紫杉醇+Ipatasertib 7.4 1.02 (0.71~1.45) 24.4 1.08 (0.73~1.58)
紫杉醇+安慰剂 6.1 24.9
以mTOR 为靶点
依维莫司 AI 治疗失败的绝经后HR+/ HER-2-晚期乳腺癌 BOLERO-2[40,60]/3 期 724 依西美坦+依维莫司 7.8 0.45 (0.38~0.54) 31.0 0.89 (0.73~1.10)
依西美坦+安慰剂 3.2 26.6
PrE0102[42] /2 期 131 氟维司群+依维莫司 10.3 0.61 (0.40~0.92) 31.4 1.31( 0.72~2.38)
氟维司群+安慰剂 5.1 28.3
GINECO[61] /2 期 111 他莫昔芬+依维莫司 8.6 0.54 (0.36~0.81) 未达到 0.45 (0.24~0.81)
他莫昔芬 4.5 32.9
SERM 治疗失败的绝经前HR+/ HER-2-晚期乳腺癌 MIRACLE[43] /2 期 199 来曲唑+依维莫司 19.4 0.64 (0.46~0.89) 未达到 0.76 (0.44~1.32)
来曲唑 12.9 未达到
初治晚期HER-2+乳腺癌 BOLERO-1[62] /3 期 719 曲妥珠+紫杉醇+依维莫司 14.95b 0.89 (0.73~1.08) - -
曲妥珠+紫杉醇+安慰剂 14.49b - -
曲妥珠+紫杉醇+依维莫司 20.27d 0.66 (0.48~0.91) - -
曲妥珠+紫杉醇+安慰剂 13.08d - -
既往接受过紫杉醇化疗的曲妥珠耐药的晚期HER-2+乳腺癌患者 BOLERO-3[63] /3 期 569 曲妥珠+长春瑞滨+依维莫司 7.0 0.78 (0.65~0.95) - -
曲妥珠+长春瑞滨+安慰剂 5.78 - -
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