The tumour suppressor p53 is mutated in more than 50% of all human cancer. Evidence over the past few years demonstrate that certain mutations in p53 acquire the p53 protein with new “Gain of Function” (GOF) properties, which promote tumourigenesis, and in particular tumour metastasis. Acquired dependency of certain cancer cells on mutant p53 was demonstrated in vitro, where knockdown of mutant p53 constrains cancer cell growth. We hypothesized that cancer cell dependency on mutant p53, defines a potential Achilles heal with therapeutic potential. Although several mutant p53 regulators have been unearthed in recent years, much remains to be described.
In order to identify key regulators of mutant p53 expression and localization, we established high-content high-throughput RNAi screens (siRNA, miRNA and lncRNA) on two human cancer cell lines. We have identified a number of potential positive and negative regulators of mutant p53, and these potential hits will be validated further experimentally and through bioinformatics analysis, to elucidate the underlying mechanisms. Our approach has the potential to identify novel regulators of mutant p53, and to define potential therapeutic approaches to target mutant p53 in human cancer cells.