Wee1 inhibition by MK1775 potentiates gemcitabine through accumulated replication stress leading to apoptosis in biliary tract cancer

Chiao Ping Chen, Chun Nan Yeh, Yi Ru Pan, Wen Kuan Huang, Yu Tien Hsiao, Chih Hong Lo, Chiao En Wu*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

3 Scopus citations

Abstract

Patients with advanced biliary tract cancer (BTC) have a poor prognosis, and novel treatments are needed. Gemcitabine, the standard of care for BTC, induces DNA damage; however, the ability of cancer cells to repair DNA dampens its effects. To improve the efficacy of gemcitabine, we combined it with MK1775, a Wee1 inhibitor that prevents activation of the G2/M checkpoint. BTC cell lines were treated with gemcitabine only or in combination with MK1775 to determine the therapeutic potential of BTC. Gemcitabine inhibited the growth and induced the apoptosis of four BTC cell lines to a greater extent when added with MK1775 than when added alone. The effects of the combination treatment were observed in both p53 wild-type and p53 mutant cell lines and were unaffected by knockdown of wild-type p53. The combination treatment increased the percentage of apoptotic cells and decreased the percentage of cells synthesizing DNA, suggesting that it caused DNA-damaged cells to accumulate and possibly die in S phase. It did not induce apoptosis when cells were arrested in mitosis using nocodazole. In a xenograft mouse model, gemcitabine plus MK1775 (but not either alone) inhibited the growth of tumors generated from inoculated BTC cells. Our results show that MK1775 highly enhances gemcitabine cytotoxicity in BTC regardless of p53 status. We suggest that the combination treatment elicits a DNA damage response and consequent apoptosis. Our preclinical study provides a basis for future clinical trials of gemcitabine plus MK1775 in patients with BTC.

Original languageEnglish
Article number115389
Pages (from-to)115389
JournalBiomedicine and Pharmacotherapy
Volume166
DOIs
StatePublished - 10 2023

Bibliographical note

Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Keywords

  • Biliary tract cancer (BTC)
  • Gemcitabine
  • MK1775
  • P53
  • Wee1
  • Animals
  • Humans
  • Biliary Tract Neoplasms/drug therapy
  • Mice
  • Tumor Suppressor Protein p53/genetics
  • Apoptosis
  • Disease Models, Animal

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