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.

Keywords: biliary tract cancer; gemcitabine resistance; p53.

Figure 1

The influence of TP53 mutation in cancer cells. p53 is a transcription factor that transactivates downstream genes responsible for cell cycle arrest, apoptosis and cell senescence. Once p53 becomes mutated (MUT), it loses wild-type (WT) p53 function. In some cases, the mutant form selectively accumulates due to loss of binding to MDM2. As p53 functions as a tetramer, the mutant and functionally defective form then dominates over the lower number of wild-type p53 protein molecules from the remaining normal allele. However, for the most part, TP53 behaves as a classical tumor suppressor gene and both alleles need to be inactivated by a combination of mutation and/or deletion. Nevertheless, some mutant forms of p53 bind to transcription factors (TFs), which transactivate genes responsible for tumor survival and drug resistance. Taken together, MUT p53 enhances tumor growth.

Figure 2

TP53 mutations in biliary tract cancers (BTCs). (A) Frequency of TP53 mutations in different studies. (B) The frequency of TP53 mutations in subtypes of BTC. (C) Collective results of available datasets of TP53 mutation in BTCs. (D) Lollipop plots for tumor TP53 mutations in BTC patients. TP53 mutations frequently occur in the DNA binding domain of p53 (red region). Black, green, pink and blue dots indicate truncating, missense, in-frame and other mutations, respectively. When different mutation types occur at a single position, the color of the circle indicates the most frequent mutation type. TAD, transactivation domain; TD, tetramerization domain. Data were accessed at cBioPortal on 3 September 2020. Please add explanation for “+, −” in image.

Figure 3

TP53/MDM2/CDKN2A alterations in biliary tract cancers (BTCs). (A) Frequency of TP53/MDM2/CDKN2A alterations in different studies. (B) The association between TP53/MDM2/CDKN2A alterations. Data were accessed at cBioPortal on 3 September 2020.

Figure 4

The impact of TP53 mutation (A,B) and CDKN2A/MDM2/TP53 alterations (C,D) on overall survival (OS) (A,C) and disease-free survival (DFS) (B,D) in biliary tract cancers (BTCs). Data were accessed at cBioPortal on 3 September 2020.

Figure 5

The proposed model of p53 impact on gemcitabine treatment. Gemcitabine induces a DNA damage response followed by activation of pATM/pATR and p53. Wild-type (WT) p53 activation can facilitate DNA repair, cell cycle arrest, apoptosis and senescence. Once p53 becomes mutated (MUT), it loses its WT function, and some mutant forms may gain function, which increases cell survival. In some cases, WT p53 is suppressed by its negative regulators such as MDM2/MDMX. Either p53 mutation or suppression by MDM2 may increase gemcitabine resistance. Dashed box indicates hypothesis.

Figure 6

Therapeutic strategy targeting p53. In p53 wild-type (WT) cancers, p53 transactivates its negative regulators, MDM2 and wild-type p53-induced phosphatase 1 (WIP1), which in turn inhibit p53 function. MDMX cooperates with MDM2 to degrade p53. MDM2 inhibitors (MDM2i), dual MDM2/MDMX inhibitors (MDM2/MDMXi) and WIP1 inhibitors (WIP1i) target negative regulators of p53 leading to p53 stabilization and activation. In contrast, p53 mutant (MUT) tumors can potentially be treated with a direct activator, such as APR-246, or indirectly with Chk1, ataxia telangiectasia related (ATR), and Wee1 inhibitors, which lead to cell death by mitotic catastrophe in MUT p53 cancers.