WEE1 억제제의 항종양 효과와 DNA 손상 반응의 조절에 의한 PARP 억제제의 민감성 강화에 관한 연구

Abstract

WEE1 plays an essential role in regulating the G2 / M checkpoint of the cell cycle by regulating CDK1 phosphorylation and is involved in stabilization and initiation of a replication fork. WEE1 is also known that regulating the activity of target CDK1 is involved in DNA repair by regulating BRCA1 phosphorylation.

WEE1 inhibitor has been reported to increase the genomic instability by inducing DNA replication stress and the G2 / M checkpoint induced by DNA damage does not function, resulting in increased the cytotoxic effect of the DNA damage agents in various carcinomas.

This study aims to investigate the anti-tumor effect of WEE1 inhibitor, AZD1775 and the mechanism of increasing the sensitivity of PARP inhibitor by modulating homologous recombination repair in triple negative breast cancer cells.

AZD1775 induced caspase-3 dependent cell death in a sensitive MDA-MB-231 cell line and induced dysregulated cell cycle activation, such as accelerating S phase initiation and early mitotic entry. In addition, AZD1775 suppressed the expression levels of proteins involved in the DNA damage repair response and inhibited the foci formation of RAD51. Thus AZD1775 led to the inhibition of homologous recombination repair, consequently prevented repair of damaged DNA. Thus, AZD1775 enhanced the cell sensitivity of the PARP inhibitor, olaparib, and this combination treatment improved the anti-tumor effect of AZD1775 and olaparib alone in the in vivo xenograft model of MDA-MB-231 cell line by compromising homologous recombination repair.

The results of this study suggest that combination therapy of AZD1775 alone or olaparib in triple negative breast cancer suggests the possibility of the anticancer effect and supports the rationale for clinical trial of combination therapy of olaparib and AZD1775.