帕博西利布
癌症研究
生物
蛋白激酶B
PI3K/AKT/mTOR通路
乳腺癌
细胞周期检查点
细胞周期
癌症
AKT1型
转移性乳腺癌
信号转导
细胞生物学
遗传学
作者
Maryam Shariati,Kurt W. Evans,Xiaofeng Zheng,Christopher A. Bristow,Patrick Kwok‐Shing Ng,Yasmeen Q. Rizvi,Coya Tapia,Fei Yang,Alessandro Carugo,Timothy P. Heffernan,Michael Peoples,Debu Tripathy,Funda Meric‐Bernstam
出处
期刊:Oncogene
[Springer Nature]
日期:2021-06-09
卷期号:40 (26): 4425-4439
被引量:12
标识
DOI:10.1038/s41388-021-01819-0
摘要
Molecular alterations in the PI3K/AKT pathway occur frequently in hormone receptor-positive breast tumors. Patients with ER-positive, HER2-negative metastatic breast cancer are often treated with CDK4/6 inhibitors such as palbociclib in combination with endocrine therapy. Although this is an effective regimen, most patients ultimately progress. The purpose of this study was identifying synthetic lethality partners that can enhance palbociclib's antitumor efficacy in the presence of PIK3CA/AKT1 mutations. We utilized a barcoded shRNA library to determine critical targets for survival in isogenic MCF7 cells with PIK3CA/AKT1 mutations. We demonstrated that the efficacy of palbociclib is reduced in the presence of PIK3CA/AKT1 mutations. We also identified that the downregulation of discoidin domain receptor 1 (DDR1) is synthetically lethal with palbociclib. DDR1 knockdown and DDR1 pharmacological inhibitor decreased cell growth and inhibited cell cycle progression in all cell lines, while enhanced the sensitivity of PIK3CA/AKT1 mutant cells to palbociclib. Combined treatment of palbociclib and 7rh further induced cell cycle arrest in PIK3CA/AKT1 mutant cell lines. In vivo, 7rh significantly enhanced palbociclib's antitumor efficacy. Our data indicates that DDR1 inhibition can augment cell cycle suppressive effect of palbociclib and could be effective strategy for targeted therapy of ER-positive, HER2-negative breast cancers with PI3K pathway activation.
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