Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers
Gemcitabine-based chemotherapy is the current standard treatment for biliary tract cancers (BTCs) and resistance to gemcitabine remains the clinical challenge. <i>TP53</i> mutation has been shown to be associated with poor clinicopathologic characteristics and survival in patients with B...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/11/1474 |
| _version_ | 1797550042429521920 |
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| author | Chiao-En Wu Yi-Ru Pan Chun-Nan Yeh John Lunec |
| author_facet | Chiao-En Wu Yi-Ru Pan Chun-Nan Yeh John Lunec |
| author_sort | Chiao-En Wu |
| collection | DOAJ |
| description | Gemcitabine-based chemotherapy is the current standard treatment for biliary tract cancers (BTCs) and resistance to gemcitabine remains the clinical challenge. <i>TP53</i> 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. |
| first_indexed | 2024-03-10T15:23:52Z |
| format | Article |
| id | doaj.art-97ad5ce061cc4ffa98f93981846809ca |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T15:23:52Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-97ad5ce061cc4ffa98f93981846809ca2023-11-20T18:15:51ZengMDPI AGBiomolecules2218-273X2020-10-011011147410.3390/biom10111474Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract CancersChiao-En Wu0Yi-Ru Pan1Chun-Nan Yeh2John Lunec3Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 333, TaiwanDepartment of General Surgery and Liver Research Center, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, TaiwanDepartment of General Surgery and Liver Research Center, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, TaiwanNewcastle University Cancer Centre, Bioscience Institute, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UKGemcitabine-based chemotherapy is the current standard treatment for biliary tract cancers (BTCs) and resistance to gemcitabine remains the clinical challenge. <i>TP53</i> 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.https://www.mdpi.com/2218-273X/10/11/1474p53gemcitabine resistancebiliary tract cancer |
| spellingShingle | Chiao-En Wu Yi-Ru Pan Chun-Nan Yeh John Lunec Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers Biomolecules p53 gemcitabine resistance biliary tract cancer |
| title | Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers |
| title_full | Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers |
| title_fullStr | Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers |
| title_full_unstemmed | Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers |
| title_short | Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers |
| title_sort | targeting p53 as a future strategy to overcome gemcitabine resistance in biliary tract cancers |
| topic | p53 gemcitabine resistance biliary tract cancer |
| url | https://www.mdpi.com/2218-273X/10/11/1474 |
| work_keys_str_mv | AT chiaoenwu targetingp53asafuturestrategytoovercomegemcitabineresistanceinbiliarytractcancers AT yirupan targetingp53asafuturestrategytoovercomegemcitabineresistanceinbiliarytractcancers AT chunnanyeh targetingp53asafuturestrategytoovercomegemcitabineresistanceinbiliarytractcancers AT johnlunec targetingp53asafuturestrategytoovercomegemcitabineresistanceinbiliarytractcancers |