Should mutant TP53 be targeted for cancer therapy?

Mutations in the TP53 tumour suppressor gene are found in similar to 50% of human cancers [1-6]. TP53 functions as a transcription factor that directly regulates the expression of similar to 500 genes, some of them involved in cell cycle arrest/cell senescence, apoptotic cell death or DNA damage repair, i.e. the cellular responses that together prevent tumorigenesis [1-6]. Defects in TP53 function not only cause tumour development but also impair the response of malignant cells to anti-cancer drugs, particularly those that induce DNA damage [1-6]. Most mutations in TP53 in human cancers cause a single amino acid substitution, usually within the DNA binding domain of the TP53 protein. These mutant TP53 proteins are often expressed at high levels in the malignant cells. Three cancer causing attributes have been postulated for mutant TP53 proteins: the inability to activate target genes controlled by wt TP53 (loss-of-function, LOF) that are critical for tumour suppression, dominant negative effects (DNE), i.e. blocking the function of wt TP53 in cells during early stages of transformation when mutant and wt TP53 proteins are co-expressed, and gain-of-function (GOF) effects whereby mutant TP53 impacts diverse cellular pathways by interacting with proteins that are not normally engaged by wt TP53 [1-6]. The GOF effects of mutant TP53 were reported to be essential for the sustained proliferation and survival of malignant cells and it was therefore proposed that agents that can remove mutant TP53 protein would have substantial therapeutic impact [7-9]. In this review article we discuss evidence for and against the value of targeting mutant TP53 protein for cancer therapy.

Automated summary

Mutations in the TP53 gene are common in human cancers and can lead to tumor development. Mutant TP53 proteins often have high expression levels in malignant cells and can impair the response of these cells to anti-cancer drugs. These mutant proteins have been found to affect cellular pathways through loss-of-function, dominant negative effects, and gain-of-function mechanisms. The sustained proliferation and survival of malignant cells rely on the gain-of-function effects of mutant TP53 proteins, suggesting that targeting these proteins could have therapeutic potential.