Synergistic And Additive Effect Of Retinoic Acid In Circumventing Resistance To P53 Restoration

TP53 mutations occur in similar to 50% of all human tumors, with increased frequency in aggressive cancers that are notoriously difficult to treat. Additionally, p53 missense mutations are remarkably predictive of refractoriness to chemo/radiotherapy in various malignancies. These observations have led to the development of mutant p53-targeting agents that restore p53 function. An important unknown is which p53-mutant tumors will respond to p53 reactivation-based therapies. Here, we found a heterogeneous impact on therapeutic response to p53 restoration, suggesting that it will unlikely be effective as a monotherapy. Through gene expression profiling of p53(R172H)-mutant lymphomas, we identified retinoic acid receptor gamma (RAR gamma) as an actionable target and demonstrated that pharmacological activation of RAR gamma with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors.