Antitumor Effect of a WEE1 Inhibitor and Potentiation of Olaparib Sensitivity by DNA Damage Response Modulation in Triple-negative Breast Cancer

Overview

Journal Sci Rep

Specialty Science

Date 2020 Jun 20

PMID 32555285

Citations 43

Authors

Dong-Hyeon Ha

Ahrum Min

Seongyeong Kim

Hyemin Jang

So Hyeon Kim

Hee-Jun Kim

Han Suk Ryu

Ja-Lok Ku

Kyung-Hun Lee

Seock-Ah Im

Affiliations

Soon will be listed here.

Abstract

Due to its regulation of CDK1/2 phosphorylation, WEE1 plays essentially roles in the regulations of G2/M checkpoint and DNA damage response (DDR). WEE1 inhibition can increase genomic instability by inducing replication stress and G2/M checkpoint inactivation, which result in increased cellular sensitivity to DNA damaging agents. We considered an increase in genomic instability induced by WEE1 inhibition might be used to augment the effects of drugs targeting DNA repair protein. Typically, PARP inhibitors are effective in germline BRCA 1/2 mutated breast and ovarian cancer, but their applicabilities in triple-negative breast cancer (TNBC) are limited. This study was conducted to investigate the anti-tumor effects of the WEE1 inhibitor, AZD1775, and the mechanism responsible for its potentiation of sensitivity to olaparib (a PARP inhibitor) via the modulation of DDR in TNBC cells. Our results suggest that AZD1775 could be used to broaden the application range of olaparib in TNBC and provide a rationale for a clinical trial of combined olaparib and AZD1775 therapy.

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