In the past fifteen years, it has become apparent that tumour-associated p53 mutations can provoke activities that are different to those resulting from simply loss of wild-type tumour-suppressing p53 function. Many of these mutant p53 proteins acquire oncogenic properties that enable them to promote invasion, metastasis, proliferation and cell survival. Here we highlight some of the emerging molecular mechanisms through which mutant p53 proteins can exert these oncogenic functions.

p53 mutations in cancer

https://www.cell.com/cancer-cell/pdf/S1535-6108(14)00037-3.pdf

Mutant p53 in Cancer: New Functions and Therapeutic Opportunities

The problem of resistance to therapy in cancer is multifaceted. Here we take a reductionist approach to define and separate the key determinants of drug resistance, which include tumour burden and growth kinetics; tumour heterogeneity; physical barriers; the immune system and the microenvironment; undruggable cancer drivers; and the many consequences of applying therapeutic pressures. We propose four general solutions to drug resistance that are based on earlier detection of tumours permitting cancer interception; adaptive monitoring during therapy; the addition of novel drugs and improved pharmacological principles that result in deeper responses; and the identification of cancer cell dependencies by high-throughput synthetic lethality screens, integration of clinico-genomic data and computational modelling. These different approaches could eventually be synthesized for each tumour at any decision point and used to inform the choice of therapy. A review of drug resistance in cancer analyses each biological determinant of resistance separately and discusses existing and new therapeutic strategies to combat the problem as a whole.

/pdf/a-view-on-drug-resistance-in-cancer-r89o0y2m1e.pdf

A view on drug resistance in cancer

Currently, around 11 million people are living with a tumour that contains an inactivating mutation of TP53 (the human gene that encodes p53) and another 11 million have tumours in which the p53 pathway is partially abrogated through the inactivation of other signalling or effector components. The p53 pathway is therefore a prime target for new cancer drug development, and several original approaches to drug discovery that could have wide applications to drug development are being used. In one approach, molecules that activate p53 by blocking protein-protein interactions with MDM2 are in early clinical development. Remarkable progress has also been made in the development of p53-binding molecules that can rescue the function of certain p53 mutants. Finally, cell-based assays are being used to discover compounds that exploit the p53 pathway by either seeking targets and compounds that show synthetic lethality with TP53 mutations or by looking for non-genotoxic activators of the p53 response.

Awakening guardian angels: drugging the p53 pathway

In its wild-type form, p53 is a major tumor suppressor whose function is critical for protection against cancer. Many human tumors carry missense mutations in the TP53 gene, encoding p53. Typically, the affected tumor cells accumulate excessive amounts of the mutant p53 protein. Various lines of evidence indicate that, in addition to abrogating the tumor suppressor functions of wild-type p53, the common types of cancer-associated p53 mutations also endow the mutant protein with new activities that can contribute actively to various stages of tumor progression and to increased resistance to anticancer treatments. Collectively, these activities are referred to as mutant p53 gain-of-function. This article addresses the biological manifestations of mutant p53 gain-of-function, the underlying molecular mechanisms, and their possible clinical implications.

/pdf/mutant-p53-gain-of-function-in-cancer-55aq9kuz1m.pdf

Dimitry B. Veprintsev

Papers

PRIMA-1 Reactivates Mutant p53 by Covalent Binding to the Core Domain