Oncotarget

Research Papers:

Prexasertib, a cell cycle checkpoint kinases 1 and 2 inhibitor, increases in vitro toxicity of PARP inhibition by preventing Rad51 foci formation in BRCA wild type high-grade serous ovarian cancer

Ethan Brill, Takuhei Yokoyama, Jayakumar Nair, Minshu Yu, Yeong-Ran Ahn and Jung-Min Lee _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:111026-111040. https://doi.org/10.18632/oncotarget.22195

Metrics: PDF 1058 views  |   HTML 2180 views  |   ?  


Abstract

Ethan Brill1,*, Takuhei Yokoyama1,*, Jayakumar Nair1, Minshu Yu1, Yeong-Ran Ahn1 and Jung-Min Lee1

1Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA

*These authors have contributed equally to this work

Correspondence to:

Jung-Min Lee, email: leej6@mail.nih.gov

Keywords: cell cycle checkpoint kinase inhibitor; prexasertib; LY2606368; PARP inhibitor; olaparib

Received: July 12, 2017    Accepted: August 31, 2017    Published: October 31, 2017

ABSTRACT

PARP inhibitors (PARPi) have been effective in high-grade serous ovarian cancer (HGSOC), although clinical activity is limited against BRCA wild type HGSOC. The nearly universal loss of normal p53 regulation in HGSOCs causes dysfunction in the G1/S checkpoint, making tumor cells reliant on Chk1-mediated G2/M cell cycle arrest for DNA repair. Therefore, Chk1 is a reasonable target for a combination strategy with PARPi in treating BRCA wild type HGSOC. Here we investigated the combination of prexasertib mesylate monohydrate (LY2606368), a Chk1 and Chk2 inhibitor, and a PARP inhibitor, olaparib, in HGSOC cell lines (OVCAR3, OV90, PEO1 and PEO4) using clinically attainable concentrations. Our findings showed combination treatment synergistically decreased cell viability in all cell lines and induced greater DNA damage and apoptosis than the control and/or monotherapies (p<0.05). Treatment with olaparib in BRCA wild type HGSOC cells caused formation of Rad51 foci, whereas the combination treatment with prexasertib inhibited transnuclear localization of Rad51, a key protein in homologous recombination repair. Overall, our data provide evidence that prexasertib and olaparib combination resulted in synergistic cytotoxic effects against BRCA wild type HGSOC cells through reduced Rad51 foci formation and greater induction of apoptosis. This may be a novel therapeutic strategy for HGSOC.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 22195