Elsevier

European Journal of Cancer

Volume 83, September 2017, Pages 258-265
European Journal of Cancer

Review
Mutant p53 as a target for cancer treatment

https://doi.org/10.1016/j.ejca.2017.06.023Get rights and content

Highlights

  • Summary of p53 mutations occurring in cancer.

  • Proof of concept of targeting mutant p53 in cancer.

  • Review of the current drugs available to target p53 and the stages in their preclinical/clinical development.

Abstract

TP53 (p53) is the single most frequently altered gene in human cancers, with mutations being present in approximately 50% of all invasive tumours. However, in some of the most difficult-to-treat cancers such as high-grade serous ovarian cancers, triple-negative breast cancers, oesophageal cancers, small-cell lung cancers and squamous cell lung cancers, p53 is mutated in at least 80% of samples. Clearly, therefore, mutant p53 protein is an important candidate target against which new anticancer treatments could be developed. Although traditionally regarded as undruggable, several compounds such as p53 reactivation and induction of massive apoptosis-1 (PRIMA-1), a methylated derivative and structural analogue of PRIMA-1, i.e. APR-246, 2-sulfonylpyrimidines such as PK11007, pyrazoles such as PK7088, zinc metallochaperone-1 (ZMC1), a third generation thiosemicarbazone developed by Critical Outcome Techonologies Inc. (COTI-2) as well as specific peptides have recently been reported to reactive mutant p53 protein by converting it to a form exhibiting wild-type properties. Consistent with the reactivation of mutant p53, these compounds have been shown to exhibit anticancer activity in preclinical models expressing mutant p53. To date, two of these compounds, i.e. APR-246 and COTI-2 have progressed to clinical trials. A phase I/IIa clinical trial with APR-246 reported no major adverse effect. Currently, APR-246 is undergoing a phase Ib/II trial in patients with advanced serous ovarian cancer, while COTI-2 is being evaluated in a phase I trial in patients with advanced gynaecological cancers. It remains to be shown however, whether any mutant p53 reactivating compound has efficacy for the treatment of human cancer.

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.

References (79)

  • X. Yu et al.

    Allele-specific p53 mutant reactivation

    Cancer Cell

    (2012)
  • K.Y. Salim et al.

    COTI-2, a new anticancer drug currently under clinical investigation, targets mutant p53 and negatively modulates the PI3K/AKT/mTOR pathway

    Eur J Cancer

    (2016)
  • A. Soragni et al.

    A designed inhibitor of p53 aggregation rescues p53 tumor suppression in ovarian carcinomas

    Cancer Cell

    (2016)
  • K. Fosgerau et al.

    Peptide therapeutics: current status and future directions

    Drug Discov Today

    (2015)
  • K.T. Bieging et al.

    Unravelling mechanisms of p53-mediated tumour suppression

    Nat Rev Cancer

    (2014)
  • F. Kruiswijk et al.

    P53 in survival, death and metabolic health: a lifeguard with a licence to kill

    Nat Rev Mol Cell Biol

    (2015)
  • E. Batchelor et al.

    Stimulus-dependent dynamics of p53 in single cells

    Mol Syst Biol

    (2011)
  • J.E. Purvis et al.

    p53 dynamics control cell fate

    Science

    (2012)
  • N.W. Fischer et al.

    p53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis

    Cell Cycle

    (2016)
  • J.C. Bourdon et al.

    P53 isoforms can regulate p53 transcriptional activity

    Genes Dev

    (2005)
  • J.C. Bourdon

    p53 isoforms change p53 paradigm

    Mol Cell Oncol

    (2014)
  • V.J. Bykov et al.

    Targeting of mutant p53 and the cellular redox balance by APR-246 as a strategy for efficient cancer therapy

    Front Oncol

    (2016)
  • B. Hong et al.

    Targeting tumor suppressor p53 for cancer therapy: strategies, challenges and opportunities

    Curr Drug Targets

    (2014)
  • A.C. Joerger et al.

    The p53 pathway: origins, inactivation in cancer, and emerging therapeutic approaches

    Annu Rev Biochem

    (2016)
  • C. Kandoth et al.

    Mutational landscape and significance across 12 major cancer types

    Nature

    (2013)
  • Cancer Genome Atlas Research Network

    Comprehensive genomic characterization of squamous cell lung cancers

    Nature

    (2012)
  • M. Peifer et al.

    Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer

    Nat Genet

    (2012)
  • Cancer Genome Atlas Network

    Comprehensive molecular portraits of human breast tumours

    Nature

    (2012)
  • Cancer Genome Atlas Research Network

    Integrated genomic analyses of ovarian carcinoma

    Nature

    (2011)
  • Y. Song et al.

    Identification of genomic alterations in oesophageal squamous cell cancer

    Nature

    (2014)
  • P.M. Do et al.

    Mutant p53 cooperates with ETS2 to promote etoposide resistance

    Genes Dev

    (2012)
  • D. Walerych et al.

    Mutant p53: one, no one, and one hundred thousand

    Front Oncol

    (2015)
  • D.S. Liu et al.

    Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation

    Nat Commun

    (2017)
  • N.T. Pfister et al.

    Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells

    Genes Dev

    (2015)
  • J. Zhu et al.

    Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth

    Nature

    (2015)
  • L. Jiang et al.

    Ferroptosis as a p53-mediated activity during tumour suppression

    Nature

    (2015)
  • D. Walerych et al.

    Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer

    Nat Cell Biol

    (2016)
  • W. Xue et al.

    Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

    Nature

    (2007)
  • A. Ventura et al.

    Restoration of p53 function leads to tumour regression in vivo

    Nature

    (2007)
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