Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient in p53Ser46 phosphorylation

► Nutlin-3 and RITA activate p53 without genotoxic stress. ► Phosphorylation of p53Ser46 plays critical roles in p53-mediated apoptosis. ► Nutlin-3 and RITA failed to induce apoptosis in the phosphorylation-deficient cells. ► They did not restore p53Ser46 phosphorylation in the phosphorylation-deficient cells. ► Thus, Ser46 phosphorylation is crucial for Nutlin-3- and RITA-mediated apoptosis.