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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 9; pp. 2198 - 2203
• Main Authors: Larsson, Connie A., Moyer, Sydney M., Liu, Bin, Michel, Keith A., Pant, Vinod, Yang, Peirong, Wong, Justin, El-Naggar, Adel K., Krahe, Ralf, Lozano, Guillermina
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27-02-2018
• Subjects: Acid resistance; Activation; Biological Sciences; Cancer therapies; Gene expression; Lymphoma; Missense mutation; Mutation; p53 Protein; Pharmacology; Radiation therapy; Recovery of function; Restoration; Retinoic acid; Targeted cancer therapy; Thermal resistance; Tumors; mutant p53; retinoic acid; p53 restoration; TNF; therapeutic response
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1719001115

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 (RARγ) as an actionable target and demonstrated that pharmacological activation of RARγ with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors.