Translating p53-based therapies for cancer into the clinic.

Inactivation of the most important tumour suppressor gene TP53 occurs in most, if not all, human cancers. Loss of functional wild-type p53 is achieved via two main mechanisms: mutation of the gene leading to an absence of tumour suppressor activity and, in some cases, gain-of-oncogenic function; or inhibition of the wild-type p53 protein mediated by overexpression of its negative regulators MDM2 and MDMX. Because of its high potency as a tumour suppressor and the dependence of at least some established tumours on its inactivation, p53 appears to be a highly attractive target for the development of new anticancer drugs.

MDM2-PROTAC versus MDM2 Inhibitors: Beyond p53 Reactivation.

In this issue of Cancer Discovery, Adams and colleagues present the discovery of a potent PROTAC, MDM2 degrader, which activates wild-type p53 leading to cancer cell death. Importantly, in a number of in vitro and in vivo experiments, the authors show that the depletion of MDM2 by PROTAC kills p53-mutant or p53-null cancer cells. See related article by Adams et al.

Mutant p53 gain of function mediates cancer immune escape that is counteracted by APR-246.

Background: p53 mutants contribute to the chronic inflammatory tumour microenvironment (TME). In this study, we address the mechanism of how p53 mutants lead to chronic inflammation in tumours and how to transform it to restore cancer immune surveillance.

Methods: Our analysis of RNA-seq data from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) project revealed that mutant p53 (mtp53) cancers correlated with chronic inflammation.

Decreased DNA Damage and Improved p53 Specificity of RITA Analogs.

Reactivation of p53 tumor-suppressor function by small molecules is an attractive strategy to defeat cancer. A potent p53-reactivating molecule RITA, which triggers p53-dependent apoptosis in human tumor cells in vitro and in vivo, exhibits p53-independent cytotoxicity due to modifications by detoxification enzyme Sulfotransferase 1A1 (SULT1A1), producing a reactive carbocation. Several synthetic modifications to RITA's heterocyclic scaffold lead to higher energy barriers for carbocation formation.