Abstract：
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 TAargeting 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.
摘要：
尽管抗HER2治疗在减少HER2阳性乳腺癌的转移和复发方面取得了重大进展，对曲妥珠单抗等药物的耐药性，帕妥珠单抗,拉帕替尼经常在接受治疗的患者中发展。先前的研究表明，PIK3CA/PTEN基因突变对PI3K-AKT信号通路的过度激活与HER2抗性有关。在这项研究中,我们介绍了一种新型的PI3K-p110αPROteasolsisTAretting嵌合体（PROTAC），该蛋白通过降解PI3K-p110α有效抑制乳腺癌细胞的增殖。在两种拉帕替尼耐药细胞系中进行测试时，JIMT1和MDA-MB-453，两者都有PIK3CA突变，PI3KPROTAC显著降低细胞增殖并诱导G1期细胞周期阻滞。重要的是,即使浓度很低，PI3KPROTAC恢复对拉帕替尼的敏感性。此外，PI3KPROTAC的功效超过了Alpelisib，一种临床上选择性的PI3K-p110α激酶抑制剂。PI3KPROTAC的优异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PI3KPROTAC可作为克服拉帕替尼耐药的有效药物.
