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Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancer

Cited 35 time in Web of Science Cited 38 time in Scopus
Authors
Jang, Na Young; Kim, Dan Hyo; Cho, Bong Jun; Choi, Eun Jung; Lee, Jong-Soo; Wu, Hong-Gyun; Chie, Eui Kyu; Kim, In Ah
Issue Date
2015-03-03
Publisher
BioMed Central
Citation
BMC Cancer, 15(1):89
Keywords
Triple-negative breast cancerRadiotherapyOlaparibPI-103PARP inhibitorPI3K inhibitor
Description
This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited.
Abstract
Abstract

Background
Triple-negative breast cancer (TNBC) shows aggressive clinical behavior, but the treatment options are limited due to lack of a specific target. TNBC shares many clinical and pathological similarities with BRCA-deficient breast cancer, for which poly(ADP-ribose) polymerase (PARP) inhibitor is effective, but PARP inhibitor alone failed to show clinical effects in patients with sporadic TNBC. Radiation induces DNA double-strand breaks, and the phosphoinositide 3-kinase (PI3K) signaling pathway has been known to regulate steady-state levels of homologous recombination. A recent preclinical study showed that PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient TNBC to PARP inhibition. Therefore, we assessed the radiosensitizing effect, and the underlying mechanism of combination treatment with PARP inhibitor olaparib and PI3K inhibitor PI-103 in BRCA-proficient TNBC cells.


Methods
MDA-MB-435S cells were divided into four treatment groups, irradiation (IR) alone, olaparib plus IR, PI-103 plus IR, and olaparib plus PI-103 plus IR. Cells were exposed to the drugs for 2 hours prior to irradiation, and the cell survival curve was obtained using a clonogenic assay. Western blotting and immunofluorescent detection of γH2AX foci were performed. Xenograft and bioluminescence imaging were carried out to assess in vivo radiosensitivity.


Results
Combined use of olaparib and PI-103 enhanced radiation-induced death of MDA-MB-435S (sensitizer enhancement ratio[SER]0.05,1.7) and MDA-MB-231-BR (SER0.05,2.1) cells and significantly reduced tumor volume in a xenograft models (P < 0.001). Treatment with PI-103 showed persistent γH2AX foci, indicating delayed repair of DNA strand breaks. PI-103 alone increased levels of poly(ADP-ribose) and phosphorylated extracellular signal-regulated kinase, and downregulated BRCA1.


Conclusions
Combined use of olaparib and PI-103 enhanced radiation-induced cell death in BRCA-proficient MDA-MB-435S and MDA-MB-231-BR cells and xenografts. TNBC patients have high incidences of locoregional relapse and distant metastasis, and radiation therapy targets both locoregional control and treatment of distant recurrences such as brain metastasis or other oligometastasis. Targeting of the PI3K signaling pathway combined with PARP inhibition maybe a feasible approach to enhance effects of radiation in BRCA-proficient TNBC.
Language
English
URI
https://hdl.handle.net/10371/100517
DOI
https://doi.org/10.1186/s12885-015-1090-7
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College of Medicine/School of Medicine (의과대학/대학원)Radiation Oncology (방사선종양학전공)Journal Papers (저널논문_방사선종양학전공)
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