Targeting mutant p53 in cancer: the latest insights

Silvia Di Agostino,Gabriella D’Orazi,Sabrina Strano,Giovanni Blandino,Giulia Fontemaggi

doi:10.1186/s13046-019-1302-0

Abstract

This commentary wishes to highlight the latest discoveries in the mutant p53 field that have been discussed in the 8th p53 Mutant Workshop 2019, held in Lyon. TP53 mutant (mutp53) proteins are involved in the pathogenesis of most human cancers. Mutp53 proteins not only lose wild-typ53 function but, in some circumstances, may acquire novel oncogenic functions, namely gain-of-function (GOF), which lead to aberrant cell proliferation, chemoresistance, disruption of tissue architecture, migration, invasion and metastasis. Decoding the TP53 mutational spectrum and mutp53 interaction with additional transcription factors will therefore help to developing and testing novel and hopefully more efficient combinatorial therapeutic approaches.

Highlights

Loss of p53 tumor suppressor functions induces accumulation of genomic alterations culminating in cancer progression, other than loosing wild-type oncosuppressor function, some mutant p53 proteins may acquire new oncogenic functions, namely gain-offunction (GOF), associated with altered p53-dependent transcriptional programs [1]
This occurred in a very special time for p53 studies since the Li-Fraumeni syndrome (LFS) was first described in 1969 and p53 itself came into being in 1979 while mutant p53 was recognized as a major event in cancer in 1989
* Correspondence: silvia.diagostino@ifo.gov.it; gdorazi@unich.it 1Oncogenomic and Epigenetic Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy 2Department of Medical Science, University ‘G. D’Annunzio, 66013 Chieti, Italy Full list of author information is available at the end of the article aspects of mutant p53 proteins can be underscored and, most importantly, how to exploit them in the decades to target cancers with mutp53 accumulation (Fig. 1)

Summary

Introduction

TP53 is the most frequently inactivated tumor suppressor gene in tumors, being mutated in over 50% of human cancer types and indirectly inactivated in many others. Loss of p53 tumor suppressor functions induces accumulation of genomic alterations culminating in cancer progression, other than loosing wild-type (wt) oncosuppressor function, some mutant p53 (mutp53) proteins may acquire new oncogenic functions, namely gain-offunction (GOF), associated with altered p53-dependent transcriptional programs [1].

Results

Conclusion