Mutations in the tumour suppressor gene p53 are present in ~50% of all human cancers. Many of these mutations cause the TP53 protein to be stabilised abnormally and accumulate in cells, and it has been proposed that this mutant p53 protein exhibits functions that are different from those of wild-type p53. Three activities have been ascribed to mutant TP53: loss of function (i.e. an inability to activate the target genes that can be activated by wt p53), dominant-negative effects (i.e. the ability of mutant p53 proteins to impair the function of wt p53 proteins as p53 functions as a tetramer) as well as gain-of-function effects (i.e. the ability of mutant p53 proteins to control processes that are not impacted by wt p53). It is still unclear which of these activities are critical for mutant p53 to drive the development and sustained growth of tumours.
It has been proposed that the gain-of-function effects of mutant p53 are critical for the sustained growth and therapy resistance of diverse cancers. If this was indeed the case drugs that could abrogate the expression or function of mutant p53 would be expected to have major impact on many cancers. To investigate this we are using Crispr mediated deletion of mutant p53 in human and mouse cancer derived cell lines and we have developed a switchable mutant p53 mouse where the allele can be switched from producing wild-type protein to R246Q (equivalent to the second most frequent mutation in human p53) mutant p53 and using different tools can be switched back from mutant p53 to wild-type p53 or, in a second strain, to a p53-deficient state. In contrast to published data, our findings thus far reveal that the gain-of-function effects of mutant p53 are not required for the sustained growth and therapy resistance of diverse cancers. Thus therapeutic interventions that could abrogate expression or function of mutant p53 are predicted not to offer significant therapeutic benefit.