ReviewMutant p53 as a target for cancer treatment
Introduction
p53 (TP53) is one of the best studied genes involved in cancer formation and/or progression. Traditionally, p53 was believed to suppress cancer formation and progression by inducing genes involved in cell cycle arrest, apoptosis or senescence or by participating in DNA repair. While these mechanisms of tumour suppression have been identified in several different model systems, more recent data suggests that p53 may also limit cancer formation via regulating metabolism, modulating reactive oxygen species (ROS) levels, altering expression of non-coding RNAs, enhancing autophagy or enhancing ferroptosis (for reviews, see refs. [1], [2], [3]).
p53 accomplishes the above processes largely by acting as a homotetrameric transcription factor, binding to specific DNA sequences and regulating gene expression. The specific genes and thus the specific processes altered as a result of binding to DNA appears to depend, at least in part, on the level of the p53 protein, its oligomerisation state, dynamics of its induction (slow, fast or pulsatile), presence of other transcriptional factors as well as the concentration of specific endogenous apoptotic-regulating proteins [4], [5], [6], [7]. The specific genes altered may also depend on the presence and concentrations of p53 isoforms, some of which may be antagonistic to full-length p53 [8], [9].
Impairment or loss of p53 function however, is widespread, if not universal in human malignancy. Impairment can occur either by mutation, gene deletion, protein sequestration by specific viral proteins, increased expression of negative regulators (e.g. MDM2 or MDM4) or alterations in upstream/downstream pathways [1], [2], [3]. Of these inactivation mechanisms, mutation and interaction with the negative regulators MDM2 and MDM4 appear to be the most important. Since loss of function in p53 occurs in most cancers, reversing this process is an attractive strategy for the development of new treatments for the disease.
Several approaches have been investigated for restoring the lost function of p53 in cancer. These include reactivation of mutant p53 to a wild-type form, depletion of mutant p53, blocking the negative regulators MDM2 and MDM4, gene therapy with vectors containing wild-type p53, identification of synthetic lethal partners for mutant p53 and treatment with compounds that promote readthrough of premature termination codons [10], [11], [12]. The aim of this article is to discuss recent developments with compounds that reactivate mutant p53 protein to a form exhibiting wild-type properties. Firstly, however, we briefly review the role of mutant p53 in malignancy.
Section snippets
p53 mutations in malignancy
Overall, p53 is believed to be mutated in approximately 50% of all human malignancies. In contrast to most tumour suppressor genes such as the adenomatous polyposis coli (APC) gene in colorectal cancer, PTEN gene (coding phosphatase and tensin homologue) and BRCA1/2 genes (coding breast cancer 1/2 proteins), which are usually inactivated by truncating or deletion-type mutations, mutations in p53 are predominantly missense [1]. Thus, the full-length form of mutant p53 is usually found in
Proof of principle
Several studies in different animal models provide proof of principle that restoration of wild-type p53 function can suppress tumour growth [29], [30], [31], [32], [33], [34]. The impact of p53 restoration on tumour growth however, appears to depend on the stage of cancer progression. Thus, in an animal model of pineoblastoma, Harajly et al. [33] found that wild-type p53 restoration induced senescence in preinvasive but not in invasive lesions. The failure to induce senescence in the invasive
Conclusion
Because of its high mutation frequency and critical role in driving cancer formation/progression, mutant p53 is a high-priority target for anticancer therapy. However, as mentioned in the Introduction above, until recently, mutant p53 was regarded as undruggable. As discussed above, this situation has now clearly changed, as several compounds have recently become available that can reactivate mutant p53 to a form with wild-type properties. Several questions however, need to be addressed in
Conflict of interest statement
JC received honoraria and research funding from Eisai Ltd.
Acknowledgements
We thank Science Foundation Ireland, Strategic Research Cluster Award (08/SRC/B1410) to Molecular Therapeutics for Cancer Ireland (MTCI), the BREAST-PREDICT (CCRC13GAL) program of the Irish Cancer Society and the Clinical Cancer Research Trust for funding this work.
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