WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability
Authors: Donye Dominguez
Lei Qin
Xia Li
Alan Long
Siqi Chen
Yi Zhang
Bin Zhang
Jie Fan
Minghui Zhang
Huirong Shi
Journal: Oncology Letters (2017)
Discipline: CLINICAL MEDICINE
Keywords: ID8; MK1775; SKOV3; Wee1-like protein kinase; monotherapy
Affiliations: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China., Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA., Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.

Abstract:  Wee1-like protein kinase (WEE1) contributes to the upstream regulation of the cyclin-dependent kinase (CDK) complexes by mediating the inactivation of CDK1 [corrected]. Increased expression of WEE1 has been associated with the poor prognosis of patients with ovarian cancer. The present study aimed at examining the in vitro and in vivo antitumor activity of MK1775, a potent pharmacological inhibitor of WEE1, as a single agent against ovarian cancer cells. The cytotoxicity of MK1775 was examined in a panel of tumor cells using MTT in vitro. Subsequently, a cell apoptosis assay was performed in ovarian cancer SKOV3 and ID8 cells to characterize the function of MK1775 in tumor cell apoptosis, under either wild-type tumor protein 53 (p53) or null p53 status. In addition, cell cycle analysis and a western blot analysis were performed to validate the effect of MK1775 on cell cycle progression and to elucidate the underlying molecular mechanism of cell death. Finally, the in vivo antitumor efficacy of MK1775 as a single agent at a clinical well-tolerated dose was determined. A dose-dependent inhibitory effect of MK1775 on tumor cell viability was determined in distinct cell lines, including B16F10, LLC1, BPS1, EG7, ID8 and SKOV3. Results from the cell cycle analysis and western blotting indicated that MK1775 abrogated the G2/M checkpoint through inhibiting the phosphorylation of CDK1 and inducing the apoptosis of ovarian cancer cells that lacked mutations in p53 and breast cancer 1 (BRCA1). Additionally, a significant antitumor effect of MK1775 was observed in C57BL/6 mice bearing syngeneic ID8 ovarian tumors. The results of the present study supported the use of MK1775 as a monotherapy agent in ovarian cancer. MK1775 was effective at inducing mitotic catastrophe, independent of p53 and BRCA1 mutations. Therefore, WEE1 inhibition by MK1775 requires additional investigation to identify novel combination approaches in ovarian cancer therapy with the current DNA damaging agents, including irradiation treatment and cell cycle checkpoint inhibitors. 

Retracted: No

PubPeer comments:
 Oncol Lett 14: 3580-3586, 2017; DOI: 10.3892 ol.2017.6584 Following the publication of this article, an interested reader drew to our attention an error in the published text: On p. 3580, the first sentence of the Abstract should have read as u201cWee1-like protein kinase (WEE1) physiologically serves a key function in maintaining the integrity of the cell genome through mediating the inactivation of cyclin-dependent kinase (CDK)1 and CDK2.u201d (i.e., u201cactivationu201d was featured incorrectly). Likewise, the first sentence in the Introduction should have read as u201cWee1-like protein kinase (WEE1) u2026 contributes to the upstream regulation of the cyclin-dependent kinase (CDK) complexes by mediating the inactivation of CDK1.u201d We apologize that these errors were allowed to remain in the paper, and regret the inconvenience that this has caused. ,