Abstract 2814: Antitumor effects of WEE1 inhibitor, AZD1775 alone or in combination with PARP inhibitor in triple negative breast cancer cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.2814-2814
• Main Authors: Ha, Dong Hyeon, Min, Arrum, Kim, Seongyeong, Kim, So Hyeon, Jang, Hyemin, Kim, Yu Jin, Jung, Daeun, Park, YoonJung, Suh, Koung Jin, Lee, Kyung-Hun, Kim, Tae-Yong Kiim, Im, Seock-Ah
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-2814

Background: Wee1 is a critical component of the G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of CDC2. Inhibition of Wee1 has been reported to enhance the cytotoxic effect of DNA damaging agents in different types of carcinomas. Especially, recent reports have shown that DNA replication stress and double strand breaks are induced by the activation of CDK1 following WEE1 inhibitor treatment. We investigated the effects and underlying mechanisms of WEE1 inhibitor, AZD1775, in Triple Negative Breast Cancer (TNBC). In addition, we examined whether AZD1775 would enhance the anti-tumor effect of PARP inhibitor in TNBC cells by modulating DNA repair activity. Methods: MTT assay was performed to investigate the antitumor effect of WEE1 inhibitor, AZD1775 alone or with PARP inhibitor in breast cancer cell lines. The regulation of DNA damage response activity by AZD1775 or/and PARP inhibitor was accessed by the comet and western blotting. The status of the S phase was evaluated by EdU-BrdU dual pulse labeling, and the drug effect was also confirmed in vivo by mouse xenograft model of TNBC. Results: AZD1775 showed heterogeneous antitumor effects among TNBC cells regardless of TP53 mutation statues. WEE1 inhibition led to accelerated S phase progression and mitotic entry in the sensitive MDA-MB-231 cells. In addition, increased DNA damage and caspase-3 dependent apoptosis were observed in sensitive cells following AZD1775 treatment. Furthermore, AZD1775 enhanced cellular sensitivity to PARP inhibitor through increase apoptosis and DNA damage accumulation. In a MDA-MB-231 xenograft model, AZD1775 impedes tumor growth as well. Conclusions: In the TNBC, the WEE1 inhibitor has a heterogeneous cytotoxic effect regardless of the p53 mutation status. In MDA-MB-231 cell, which is a sensitive TNBC cells to WEE1 inhibitor AZD1775, the progression of the cell cycle was accelerated and the aberrant DNA content was increased. This resulted in DNA damage, which led to cell death, and this effect could be applied in vivo. In addition, we investigated that WEE1 inhibition can increase PARP inhibitor sensitivity in TNBC cells via increasing accumulation of DNA damage. Our results provide a rationale for the future clinical trials of PARP inhibitor combined with WEE1 inhibition in triple negative breast cancer. Citation Format: Dong Hyeon Ha, Arrum Min, Seongyeong Kim, So Hyeon Kim, Hyemin Jang, Yu Jin Kim, Daeun Jung, YoonJung Park