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Targeting P53 as a future strategy to overcome gemcitabine resistance in biliary tract cancers

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.

Publication metadata

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


DOI: 10.3390/biom10111474

PubMed id: 33113997


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