Translational approaches targeting the p53 pathway for anti-cancer therapy

Abstract

The p53 tumour suppressor blocks cancer development by triggering apoptosis or cellular senescence in response to oncogenic stress or DNA damage. Consequently, the p53 signalling pathway is virtually always inactivated in human cancer cells. This unifying feature has commenced tremendous efforts to develop p53-based anti-cancer therapies. Different strategies exist that are adapted to the mechanisms of p53 inactivation. In p53-mutated tumours, delivery of wild-type p53 by adenovirus-based gene therapy is now practised in China. Also, remarkable progress has been made in the development of p53-binding drugs that can rescue and reactivate the function of mutant or misfolded p53. Other biologic approaches include the development of oncolytic viruses that are designed to specifically replicate in and kill p53-defective cells. Inactivation of wt-p53 frequently results from dysregulation of MDM2, an E3 ligase that regulates p53 levels. Small-molecule drugs that inhibit the interaction of MDM2 and p53 and block p53 degradation are currently tested in clinical trials. This survey highlights the recent developments that attempt to modulate the function of p53 and outlines strategies that are being investigated for pharmacological intervention in the p53 pathway.

Figure 1

Spectrum of p53 mutations in human cancers. Mutation data from the curated UMD TP53 mutation database (http://p53.free.fr/database) including 25 905 human tumours were processed, and the mutation frequency of each amino acid in p53 is depicted. Specific hot spot mutations, the location of the mutation within the p53 domain structure and their impact on p53 are indicated. Point mutations can be categorized in contact and structural mutations. Contact mutations are located at the interface with the major and minor grooves of DNA, whereas structural mutations mostly result in destabilization of p53. TAD: transactivation domain, PRD: proline-rich domain, DBD: DNA-binding domain, TD: tetramerization domain, BD: basic domain.

Figure 2

Tumour suppressor p53 regulation and signalling. Activation of the transcription factor p53 is predominantly mediated by stabilization, mostly due to phosphorylation by upstream kinases such as ATM/ATR or Chk1/2. As a tetramer the stabilized p53 binds to DNA consensus sequences and induces transcription of huge number of different target genes involved apoptosis, senescence or DNA repair. One of the target genes is the ubiquitin E3 ligase MDM2 that regulates the proteolytic degradation of p53 in a negative feedback loop. This negative regulation is facilitated by MDMX and attenuated by p14^Arf that interferes with MDM2-mediated down-regulation of p53.