PARP抑制剂
奥拉帕尼
胰腺癌
癌症研究
mTORC2型
癌症
聚ADP核糖聚合酶
生物
DNA修复
PI3K/AKT/mTOR通路
医学
内科学
信号转导
细胞生物学
聚合酶
mTORC1型
遗传学
DNA
作者
Chiwen Bu,Le Zhao,L. Wang,Zhenxin Yu,Jiahua Zhou
出处
期刊:Oncology Research
[Cognizant, LLC]
日期:2023-01-01
卷期号:31 (4): 495-503
被引量:1
标识
DOI:10.32604/or.2023.029309
摘要
Pancreatic cancer is one of the most aggressive cancers with a median survival time of less than 5 months, and conventional chemotherapeutics are the main treatment strategy. Poly(ADP-ribose) polymerase (PARP) inhibitors have been recently approved for BRCA1/2-mutant pancreatic cancer, opening a new era for targeted therapy for this disease. However, most pancreatic cancer patients carry wild-type BRCA1/2 with resistance to PARP inhibitors. Here, we reported that mammalian target of rapamycin complex 2 (mTORC2) kinase is overexpressed in pancreatic cancer tissues and promotes pancreatic cancer cell growth and invasion. Moreover, we found that knockdown of the mTORC2 obligate subunit Rictor sensitized pancreatic cancer cells to the PARP inhibitor olaparib. Mechanistically, we showed that mTORC2 positively regulates homologous recombination (HR) repair by modulating BRCA1 recruitment to DNA double-strand breaks (DSBs). In addition, we confirmed that combination treatment with the mTORC2 inhibitor PP242 and the PARP inhibitor olaparib synergistically inhibited pancreatic cancer growth in vivo. Thus, this study provides a novel target and strategy for optimizing PARP inhibitor efficiency in pancreatic cancers.
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