What do we need to know and understand about p53 to improve its clinical value?

Abstract

Few proteins are more studied than the p53 tumour suppressor, but what have we learned from these studies and what do we really know about p53 that can benefit clinical practice? The DNA sequence encoding p53 is frequently mutated in cancers but the functional outcomes of single mutations, in respect to loss or gain of different activities, especially in relation to immune evasion, are not clear. This illustrates p53's complexity which even after 40 years keeps providing surprises, but also explains why it has not yet lived up to its potential to benefit cancer treatment. We have reassessed a few key experiments that shaped the p53 field and we take a closer look at the interpretations of these experiments: what they have taught us, the resulting dogmas, and their potential clinical importance. One outcome is a more dynamic view of p53 in terms of its activity, its regulation, and downstream effectors, which will benefit the clinical application of p53 for diagnosis, prognosis, and therapy. Mutations and regulatory factors can have different effects on p53 activity depending on context, important but neglected aspects when interpreting p53 and its pathways in cancers. Even though p53 is undoubtedly unique as a multifunctional hub in different cellular pathways, the concept of a factor taking up different functions within a regulatory pathway during different conditions is not. In this sense, p53 continues to lead the way for a better understanding of the cellular and molecular mechanisms underlying cancer development in vivo. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

“…The p53 gene has evolved from an ancestral p53/p63/p73 gene, which gave rise to three p53-related genes, with distinct roles in mammals ( Belyi et al 2010 ; Rutkowski et al 2010 ; Karakostis et al 2016 ; Siau et al 2016 ; Hendler et al 2021 ). The tp53 transcription factor is a tumor suppressor with key roles in oncogenesis ( Mantovani et al 2019 ; Salomao et al 2021 ). It involves two N-terminal transactivation domains (TAD I and TAD II), a DNA-binding domain (DBD), and a C-terminal oligomerization domain ( Wallace et al 2006 ; Logotheti et al 2010 ).…”

“…In addition, numerous cellular and animal model studies indicate that an unbalance in p53 isoform expression causes cancer, premature aging, and degenerative diseases ( Fujita 2019 ). An abnormal expression of p53 isoforms, or mis-regulation of posttranslational modifications (PTMs) mediating the interactions of p53 pathway, may be induced by mutations leading to carcinogenesis ( Khoury and Bourdon 2011 ; Karakostis et al 2019 ; Salomao et al 2021 ). Importantly, experiments on mice have shown that extra copies of the p53 gene can be introduced to generate “super p53” animals carrying three or four functional copies of p53, accurately reproducing the behavior of the endogenous gene but with an enhanced response to DNA damage ( Garcia-Cao et al 2002 ; Moding et al 2016 ).…”

Clinical and Immunological Effects of p53-Targeting Vaccines

“…For tumors with mutant p53, therapeutic agents are developed to reactivate mutant p53 or promote its degradation ( Chen et al, 2021 ). Targeting the p53 signaling pathway has been extensively reviewed by a number of investigators ( Hernández Borrero and El-Deiry, 2021 ; Huang, 2021 ; Liu et al, 2021 ; Salomao et al, 2021 ). At least theoretically, therapeutic restoration of inactivated tumor suppressors is more challenging than inhibiting an oncogenic target.…”

Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets

“…As expected, the dynamic presence of these genes on the mutational cancer map, has made the p53 pathway-and especially the TP53 component-an attractive therapeutic target. Among a plethora of p53-targeting strategies, the most promising fall into one of the following categories: (i) restoring the function of p53 protein or (ii) impeding the interaction between p53 and its main negative regulator, the MDM2 E3 ubiquitin ligase [35,59,60]. In this context, eprenetapopt (APR-246), a mutant-p53 conformation resetting agent, is probably the most promising compound [61] and the only therapy of this category that is currently being tested in a phase III clinical trial (NCT03745716); on the other hand, a phase III trial of idasanutlin (NCT02545283), another emerging MDM2 inhibitor, was recently terminated due to low efficacy.…”