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Lookup NU author(s): Professor John LunecORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.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.
Author(s): Wu C-E, Pan Y-R, Yeh C-N, Lunec J
Publication type: Article
Publication status: Published
Journal: Biomolecules
Year: 2020
Volume: 10
Issue: 11
Pages: 1-17
Online publication date: 23/10/2020
Acceptance date: 21/10/2020
Date deposited: 09/11/2020
ISSN (electronic): 2218-273X
Publisher: MDPI AG
URL: https://doi.org/10.3390/biom10111474
DOI: 10.3390/biom10111474
PubMed id: 33113997
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