Abstract 4420: Small-molecule inhibition of Wee1 kinase by AZD1775 selectively sensitizes human papilloma virus (HPV)-associated cervical cancer to DNA-damaging therapies

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-07, Vol.79 (13_Supplement), p.4420-4420
• Main Authors: Kobayashi, Osamu, Ikeda, Yuji, Okuma, Yuki, Hayashi, Nobuki, Nakajima, Takahiro, Asai-Sato, Mikiko, Kawana, Kei
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2019-4420

Objective: Wee1 regulate G2-M checkpoint of cell-cycle Inhibition of Wee1 promotes cell mitosis without DNA repair in cases with TP53 deficiency Since human papillomavirus (HPV) E6 involves the inactivation of p53, we aimed to evaluate effects of Wee1 inhibitor on cervical cancer. Material and Methods: Expression level of Wee1 in cervical cancer was evaluated using Oncomine Cervical cancer cell lines, Caski (HPV16+), SiHa (HPV16+) and C33A (HPV-, P53 mut) and LNCap (HPV-, P53 wt, prostate cancer) were used. After exposure to either Wee1 inhibitor (AZD1775), cisplatin, or both, cell surviving rate was evaluated by MTT assay and expression levels of Wee1 and cell cycle related proteins were evaluated by western blotting cell cycle status in cell lines were observed by flow cytometry. Results: High expression of Wee1 in cervical cancer was clinically observed among ten cancer species. Stepwise treatment of AZD1775 promoted significant cell death induction, compared with exposure to cisplatin alone in HPV-positive cells (Caski and Siha); however no effect on cell death in HPV-negative cells (C33A and LNCap). In addition, expression level of pCDC2 was reduced after exposure to AZD1775, indicating induction of cell mitosis without DNA repair. Conclusion: Our results indicate the therapeutic potential of cervical cancer treatment by Wee1 inhibition. Synergistic effect of Wee1 inhibition with conventional treatments (CCRT or chemotherapy) may be a new strategy to improve the prognosis in cervical cancer. Citation Format: Osamu Kobayashi, Yuji Ikeda, Yuki Okuma, Nobuki Hayashi, Takahiro Nakajima, Mikiko Asai-Sato, Kei Kawana. Small-molecule inhibition of Wee1 kinase by AZD1775 selectively sensitizes human papilloma virus (HPV)-associated cervical cancer to DNA-damaging therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4420.