尽管抗 HER2 疗法在减少 HER2 阳性乳腺癌的转移和复发方面取得了显着进展，但接受治疗的患者经常出现对曲妥珠单抗、帕妥珠单抗和拉帕替尼等药物的耐药性。先前的研究表明，PIK3CA/PTEN 基因突变引起的 PI3K-AKT 信号通路过度激活与 HER2 耐药有关。在这项研究中，我们介绍了一种新型的PI3K-p110α蛋白水解靶向嵌合体（PROTAC），它通过降解PI3K-p110α来有效抑制乳腺癌细胞的增殖。当在两种拉帕替尼耐药细胞系 JIMT1 和 MDA-MB-453（两者均含有 PIK3CA 突变）中进行测试时，PI3K PROTAC 显着减少细胞增殖并诱导 G1 期细胞周期停滞。重要的是，即使在非常低的浓度下，PI3K PROTAC 也能恢复对拉帕替尼的敏感性。此外，PI3K PROTAC在临床上的疗效超过了选择性PI3K-p110α激酶抑制剂Alpelisib。 PI3K PROTAC 的卓越性能也在拉帕替尼耐药乳腺癌异种移植肿瘤和患者来源的乳腺癌类器官 (PDO) 中得到证实。总之，这项研究表明，我们合成的新型 PI3K PROTAC 可以作为克服拉帕替尼耐药性的有效药物。版权所有 © 2024。由 Elsevier B.V. 出版。

Although anti-HER2 therapy has made significant strides in reducing metastasis and relapse in HER2-positive breast cancer, resistance to agents like trastuzumab, pertuzumab, and lapatinib frequently develops in patients undergoing treatment. Previous studies suggest that the hyperactivation of the PI3K-AKT signaling pathway by PIK3CA/PTEN gene mutations is implicated in HER2 resistance. In this study, we introduce a novel PI3K-p110α PROteolysis TArgeting Chimera (PROTAC) that effectively inhibits the proliferation of breast cancer cells by degrading PI3K-p110α. When tested in two lapatinib-resistant cell lines, JIMT1 and MDA-MB-453, both of which harbor PIK3CA mutations, the PI3K PROTAC notably reduced cell proliferation and induced G1 phase cell cycle arrest. Importantly, even at very low concentrations, PI3K PROTAC restored sensitivity to lapatinib. Furthermore, the efficacy of PI3K PROTAC surpassed that of Alpelisib, a selective PI3K-p110α kinase inhibitor in clinic. The superior performance of PI3K PROTAC was also confirmed in lapatinib-resistant breast cancer xenograft tumors and patient-derived breast cancer organoids (PDOs). In conclusion, this study reveals that the novel PI3K PROTAC we synthesized could serve as an effective agent to overcome lapatinib resistance.Copyright © 2024. Published by Elsevier B.V.