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

Abstract

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.

WIP1 Inhibition by GSK2830371 Potentiates HDM201 through Enhanced p53 Phosphorylation and Activation in Liver Adenocarcinoma Cells

“…Pemigatinib (an FGFR2 inhibitor) demonstrated activity in previously treated advanced cholangiocarcinoma based on a phase 2 trial and was approved by the US FDA in 2020 [10], but only 10-15% of patients with iCCA have the FGFR2 fusion gene [11]. Therefore, this treatment gap identifies iCCA as a priority for exploring novel therapeutic drugs or regimens for advanced or refractory iCCA [12][13][14].…”

“…We have previously reported the anti-cancer activity of MDM2i in combination with GSK2830371 in cutaneous melanoma and showed that GSK2830371 potentiates the effect of MDM2i on melanoma cells by increasing the function and stability of p53 in a p53-dependent manner [21]. As more than half of iCCA are WT p53 [13], we investigated the in vitro activity of HDM201 and GSK2830371 in p53 WT iCCA to explore the potential of this combination for future clinical trials.…”

Transient Response of Olaparib on Pulmonary Artery Sarcoma Harboring Multiple Homologous Recombinant Repair Gene Alterations

“…MDM2 has been reported to be associated with tumorigenesis in multiple solid tumors and sarcoma, as it inhibits the function of p53 (a tumor suppressor) via ubiquitination, leading to proteasomal degradation. Targeting MDM2 alone or in combination with other agents could be a therapeutic strategy in cancer treatment [ 16 , 17 ]. However, MDM2 inhibitors are still under investigation in early clinical trials and are clinically unavailable [ 17 , 18 ].…”

“…Targeting MDM2 alone or in combination with other agents could be a therapeutic strategy in cancer treatment [ 16 , 17 ]. However, MDM2 inhibitors are still under investigation in early clinical trials and are clinically unavailable [ 17 , 18 ]. In addition, the homozygous deletion of CDKN2A and hemizygous of RB1 were observed, and CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) may be an off-label option [ 19 ].…”

Cutting Edge Research for Exploration of Biomolecules for Gemcitabine-Based Chemo-Resistant Advanced Bile Duct Cancer: From Basic Study to Clinical Trial

“…Palliative chemotherapy with cisplatin and gemcitabine (GEM) has been the standard of care for patients with unresectable cancers since 2010 and no breakthrough progress in this challenging disease in the era of targeted therapy and immunotherapy [ 2 ]. In order to serve as a reference for further research to overcome GEM-resistance and provide novel treatment strategies, this Special Issue entitled “Cutting-Edge Research for Exploration of Biomolecules for Gemcitabine-Based Chemoresistant Advanced Bile Duct Cancers: From Basic Study to Clinical Trial” aimed to integrate the cutting-edge research and expand knowledge on a wide range of topics, including bioinformatics [ 3 ], clinical trials [ 4 ], p. 53 [ 5 ], micro-RNA [ 6 ], and other associated studies [ 7 ].…”