PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer

KIZ OpenIR > 科研部门 > 肿瘤生物学（陈策实）

	PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer
	Zhang, HY; Zhang, LL; He, YA; Jiang, DW; Sun, J; Luo, QM; Liang, HC; Wang, TT; Li, FB; Tang, Y; Yang, ZM; Liu, WJ; Rao, Y; Chen, CS
	2024
发表期刊	CANCER LETTERS
ISSN	0304-3835
卷号	598
摘要	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-p110 alpha Proteolysis TAargeting Chimera (PROTAC) that effectively inhibits the proliferation of breast cancer cells by degrading PI3K-p110 alpha. 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-p110 alpha 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.
收录类别	sci
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/14295
专题	科研部门_肿瘤生物学（陈策实）
推荐引用方式 GB/T 7714	Zhang, HY,Zhang, LL,He, YA,et al. PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer[J]. CANCER LETTERS,2024,598.
APA	Zhang, HY.,Zhang, LL.,He, YA.,Jiang, DW.,Sun, J.,...&Chen, CS.(2024).PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer.CANCER LETTERS,598.
MLA	Zhang, HY,et al."PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer".CANCER LETTERS 598(2024).

条目包含的文件
文件名称/大小	文献类型	版本类型	开放类型	使用许可
2024073132.pdf（11054KB）	期刊论文	出版稿	开放获取	CC BY-NC-SA	请求全文