Synergistic and additive effect of retinoic acid in circumventing resistance to p53 restoration.

ABSTRACT: TP53 mutations occur in ?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 p53R172H -mutant lymphomas, we identified retinoic acid receptor gamma (RAR?) as an actionable target and demonstrated that pharmacological activation of RAR? with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors.

SUBMITTER: Larsson CA 

PROVIDER: S-EPMC5834709 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature