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Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers

1
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
2
Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, Taiwan
3
Newcastle University Cancer Centre, Bioscience Institute, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
*
Authors to whom correspondence should be addressed.
Biomolecules 2020, 10(11), 1474; https://doi.org/10.3390/biom10111474
Received: 28 September 2020 / Revised: 20 October 2020 / Accepted: 21 October 2020 / Published: 23 October 2020
Gemcitabine-based chemotherapy is the current standard treatment for biliary tract cancers (BTCs) and resistance to gemcitabine remains the clinical challenge. TP53 mutation has been shown to be associated with poor clinicopathologic characteristics and survival in patients with BTCs, indicating that p53 plays an important role in the treatment of these cancers. Herein, we comprehensively reviewed previous BTC preclinical research and early clinical trials in terms of p53, as well as novel p53-targeted treatment, alone or in combination with either chemotherapy or other targeted therapies in BTCs. Preclinical studies have demonstrated that p53 mutations in BTCs are associated with enhanced gemcitabine resistance, therefore targeting p53 may be a novel therapeutic strategy for treatment of BTCs. Directly targeting mutant p53 by p53 activators, or indirectly by targeting cell cycle checkpoint proteins (Chk1, ataxia telangiectasia related (ATR), and Wee1) leading to synthetic lethality, may be potential future strategies for gemcitabine-resistant p53 mutated BTCs. In contrast, for wild-type p53 BTCs, activation of p53 by inhibition of its negative regulators (MDM2 and wild-type p53-induced phosphatase 1 (WIP1)) may be alternative options. Combination therapies consisting of standard cytotoxic drugs and novel small molecules targeting p53 and related signaling pathways may be the future key standard approach to beat cancer. View Full-Text
Keywords: p53; gemcitabine resistance; biliary tract cancer p53; gemcitabine resistance; biliary tract cancer
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MDPI and ACS Style

Wu, C.-E.; Pan, Y.-R.; Yeh, C.-N.; Lunec, J. Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers. Biomolecules 2020, 10, 1474. https://doi.org/10.3390/biom10111474

AMA Style

Wu C-E, Pan Y-R, Yeh C-N, Lunec J. Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers. Biomolecules. 2020; 10(11):1474. https://doi.org/10.3390/biom10111474

Chicago/Turabian Style

Wu, Chiao-En; Pan, Yi-Ru; Yeh, Chun-Nan; Lunec, John. 2020. "Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers" Biomolecules 10, no. 11: 1474. https://doi.org/10.3390/biom10111474

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