Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process

Abstract

Urothelial carcinoma (UC) is characterized by a high incidence of TP53 mutation, and overcoming resistance to cisplatin-based chemotherapy in UC is a major concern. Wee1 is a G2/M phase regulator that controls the DNA damage response to chemotherapy in TP53-mutant cancers. The combination of Wee1 blockade with cisplatin has shown synergistic efficacy in several types of cancers, but little is known regarding UC. The antitumor efficacy of the Wee1 inhibitor (AZD-1775) alone or in combination with cisplatin was evaluated in UC cell lines and a xenograft mouse model. AZD-1775 enhanced the anticancer activity of cisplatin by increasing cellular apoptosis. AZD-1775 inhibited the G2/M checkpoint, improving the sensitivity of mutant TP53 UC cells to cisplatin by enhancing the DNA damage process. We confirmed that AZD-1775 combined with cisplatin reduced tumor volume and proliferation activity and increased the markers of cell apoptosis and DNA damage in the mouse xenograft model. In summary, the Wee1 inhibitor AZD-1775 combined with cisplatin elicited a promising anticancer efficacy in UC, and constitutes an innovative and promising therapeutic strategy.

Identification of prognostic and diagnostic signatures for cancer and acute myocardial infarction: multi-omics approaches for deciphering heterogeneity to enhance patient management

“…In our study, our findings suggest that WEE1, PYHIN1, SEC61A2, and HAL derived from monocytes may serve as a potential predictor for AMI and cancer prognosis. WEE1, a protein kinase involved in cell cycle regulation, acts as a critical regulator of the DNA damage response pathway and plays a crucial role in maintaining genomic stability ( Okabe et al, 2023 ; Su et al, 2023 ). Its overexpression has been observed in various tumor types, contributing to tumor growth, chemoresistance, and poor prognosis.…”

Crosstalk between Wnt/β-catenin signaling pathway and DNA damage response in cancer: a new direction for overcoming therapy resistance

“…DDR has been extensively involved in regulation of cell senescence, carcinogenesis, and cancer progression as well as influencing the efficacy of cancer radiotherapy and chemotherapy. As the majority of anti-tumor therapies primarily target the genomic DNA of cancer cells, enhancement of DDR is closely related to their therapeutic efficacy ( Lord and Ashworth, 2012 ; Su et al, 2023 ; Traphagen et al, 2023 ).…”