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

// Dong Wang 1, 2 , Min Wang 1 , Nan Jiang 1 , Yuan Zhang 1 , Xing Bian 1 , Xiaoqing Wang 1 , Thomas M. Roberts 3, 4 , Jean J. Zhao 3, 4 , Pixu Liu 1 , Hailing Cheng 1 1 Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China 2 Department of Histology and Embryology, Binzhou Medical College, Yantai 264000, China 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA Correspondence to: Hailing Cheng, e-mail: hailingcheng_dmu@163.com Pixu Liu, e-mail: pixu_liu@dmu.edu.cn Jean J. Zhao, e-mail: jean_zhao@dfci.harvard.edu Keywords: ovarian cancer, BKM120, Olaparib, BRCA, combination therapy Received: October 02, 2015      Accepted: January 23, 2016      Published: February 21, 2016 ABSTRACT 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.