2. Academic Validation
  3. Wee1 inhibition by MK1775 potentiates gemcitabine through accumulated replication stress leading to apoptosis in biliary tract cancer

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

  • Biomed Pharmacother. 2023 Aug 31;166:115389. doi: 10.1016/j.biopha.2023.115389.
Chiao-Ping Chen 1,  Chun-Nan Yeh 2,  Yi-Ru Pan 3,  Wen-Kuan Huang 1,  Yu-Tien Hsiao 1,  Chih-Hong Lo 1,  Chiao-En Wu 4
Affiliations

Affiliations

  • 1 Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
  • 2 Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of General Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
  • 3 Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of General Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  • 4 Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan. Electronic address: jiaoen@gmail.com.
PMID: 37659202 DOI: 10.1016/j.biopha.2023.115389
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.

Keywords

Biliary tract cancer (BTC); Gemcitabine; MK1775; P53; Wee1.

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