Mutations in the tumour suppressor TP53 (TRP53 in mice) are common in most cancers, and confer poor responses to therapy. TP53 mutations are postulated to contribute to blood cancers in three, not mutually exclusive, ways. These include 1. loss of tumour suppressor functions, 2. dominant-negative effects on wild-type (wt) TP53 and 3. neomorphic gain-of-functions (GOF) effects. Understanding how mutant TP53 functions in cancer is critical to inform new therapeutic approaches. To address this, we generated two sophisticated mouse models in which we engineered the endogenous Trp53 locus to permit switching between different TRP53 states. By crossing these mice to cancer-prone models we could address how mutant TRP53 contributes to cancer growth and responses to therapy.
Our data suggest that mutant TRP53 does not have GOF effects that are required for tumour growth. Therefore, drugs that degrade or inactivate mutant TP53 would not have therapeutic benefit. However, drugs that could restore wt TP53 functions would be capable of killing cancers.