Anti-Tumor Effects of Wee1 Kinase Inhibitor with Radiotherapy in Human Cervical Cancer

Yoo-Young Lee,Jeong-Won Lee,Jae Ryoung Hwang,Ji-Yoon Ryu,Byoung- Gie Kim,Won Park,Hye-Kyung Jeon,Sung-Won Shin,Changhoon Choi,Jung-Joo Choi,Young-Jae Cho,Tae-Joong Kim,Chel Hun Choi,Duk-Soo Bae

doi:10.1038/s41598-019-51959-3

Yoo-Young Lee, Jeong-Won Lee + Show 12 more

Open Access

https://doi.org/10.1038/s41598-019-51959-3

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Abstract

Although the concurrent use of a chemotherapeutic agent and radiotherapy improves survival in patients with locally advanced or recurrent cervical cancer, severe side effects related to chemotherapy are frequent and may result in a low quality of life for the patients. In this study, we investigated the effects of a combination of Wee1 inhibitor (AZD1775) and irradiation in cervical cancer. In vitro effects of AZD1775 with irradiation in human cervical cancer cells were assessed by clonogenic survival and apoptosis assays. The effects on DNA damage response signaling and the cell cycle were also explored. Tumor growth delay was evaluated to investigate the in vivo effects of AZD1775 with irradiation in cervical cancer mouse models, including xenografts and patient-derived xenografts (PDXs). The co-treatment of AZD1775 and irradiation significantly decreased clonogenic survival and increased apoptosis in cervical cancer cells. These effects were associated with G2 checkpoint abrogation which resulted in persistent DNA damage. Both in the xenografts and the PDXs, the co-treatment significantly decreased tumor growth compared tothe irradiation alone (p < 0.05). These results demonstrate that the Wee1 inhibitor (AZD1775) can be considered as a potential alternative as a radiosensitizer in cervical cancer instead of a chemotherapeutic agent such as cisplatin.

Highlights

Concurrent chemoradiation (CCRT) is a standard treatment for locally advanced or recurrent cervical cancer
Our data show for the first time that Wee[1] inhibition by AZD1775 abrogates the prolonged the G2 checkpoint induced by radiation therapy (RT) and leads to dramatic radiosensitization in cervical cancer
Due to the potential toxicity from chemotherapeutic agents, replacing chemotherapy in CCRT with targeted agents is an attractive alternative for treatment of cancer types that are usually treated with RT, such as head and neck, cervical, and anal cancers

Summary

Introduction

Concurrent chemoradiation (CCRT) is a standard treatment for locally advanced or recurrent cervical cancer. CCRT is tolerable in most patients, the addition of cisplatin to irradiation may cause acute toxicities such as nephrotoxicity and ototoxicity It has been associated with a higher rate of hematologic and gastrointestinal adverse effects compared to RT alone[2,3]. Many clinical trials have tested the ability of the Wee[1] inhibitor AZD1775 to impair the growth of different types of cancer alone or in combination with other cytostatic agents (e.g., cisplatin, paclitaxel, 5-fluorouracil, and topotecan)[8] In this context, the co-treatment with a Wee 1 inhibitor, which is a G2 checkpoint inhibitor, with IR for cervical cancer may have a significant dampening effect on the recovery of cancer cells from the RT-induced DNA damage that may eventually lead to cell death. Our data show for the first time that Wee[1] inhibition by AZD1775 abrogates the prolonged the G2 checkpoint induced by RT and leads to dramatic radiosensitization in cervical cancer

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