Antitumor effect of a WEE1 inhibitor and potentiation of olaparib sensitivity by DNA damage response modulation in triple-negative breast cancer

• Published in: Scientific reports Vol. 10; no. 1; p. 9930
• Main Authors: Ha, Dong-Hyeon, Min, Ahrum, Kim, Seongyeong, Jang, Hyemin, Kim, So Hyeon, Kim, Hee-Jun, Ryu, Han Suk, Ku, Ja-Lok, Lee, Kyung-Hun, Im, Seock-Ah
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.06.2020; Nature Publishing Group
• Subjects: 13/109; 13/2; 13/31; 14/1; 14/19; 38/109; 631/337/1427/2566; 631/67/1347; 64/60; 82/1; Animals; Antitumor activity; Apoptosis; Breast cancer; Cell Cycle; Cell Cycle Proteins - antagonists & inhibitors; Cell Proliferation; Deoxyribonucleic acid; DNA; DNA Damage; DNA Repair; Drug delivery; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Enzyme Inhibitors - pharmacology; Female; Gene Expression Regulation, Neoplastic; Genomic instability; Humanities and Social Sciences; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; multidisciplinary; Ovarian cancer; Phosphorylation; Phthalazines - pharmacology; Piperazines - pharmacology; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrazoles - pharmacology; Pyrimidinones - pharmacology; Science; Science (multidisciplinary); Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-66018-5

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.