Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer

被引：65

作者：

Wang, Dong ^{[1
,2
]}

Wang, Min ^{[1
]}

Jiang, Nan ^{[1
]}

Zhang, Yuan ^{[1
]}

Bian, Xing ^{[1
]}

Wang, Xiaoqing ^{[1
]}

Roberts, Thomas M. ^{[3
,4
]}

Zhao, Jean J. ^{[3
,4
]}

Liu, Pixu ^{[1
]}

Cheng, Hailing ^{[1
]}

机构：

[1] Dalian Med Univ, Inst Canc, Inst Canc Stem Cell, Hosp 2, Dalian 116044, Peoples R China

[2] Dept Histol & Embryol, Binzhou Med Coll, Yantai 264000, Peoples R China

[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

来源：

ONCOTARGET | 2016年 / 7卷 / 11期

基金：

中国国家自然科学基金;

关键词：

ovarian cancer; BKM120; Olaparib; BRCA; combination therapy; NEGATIVE BREAST-CANCER; DNA-REPAIR; PHASE-I; NVP-BKM120; RESISTANCE; CELLS; IDENTIFICATION; COMBINATION; EXPRESSION; THERAPY;

D O I：

10.18632/oncotarget.7549

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition.

引用

页码：13153 / 13166

页数：14

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