Nonsense-mediated mRNA decay inhibition synergizes with MDM2 inhibition to suppress TP53 wild-type cancer cells in p53 isoform-dependent manner

The restoration of the normal function of the tumour suppressors, such as p53, is an important strategy in tumour therapeutics. Nonsense-mediated mRNA decay (NMD) inhibition by NMD inhibitor (NMDi) upregulates functional p53 isoforms, p53β and p53γ, and activates the p53 pathway. XR-2, a novel mouse double minute 2 homolog (MDM2) inhibitor, can disrupt the interaction between p53 and MDM2, thus decreasing the MDM2-mediated degradation of p53 and increasing the p53 protein levels. However, the combined effects of these two agents have not been thoroughly explored. This study combined XR-2 and NMDi in four TP53 wild-types and four TP53-mutated cancer cell lines. The combination of these two agents achieved significant synergistic effects on TP53 wild-type cancer cell lines by transactivating p53 target genes, inducing apoptosis, cell-cycle arrest and DNA damage repair. The p53β isoform induced by NMDi enhances the transactivation ability of p53α induced by XR-2, which partially explains the mechanism of the synergistic effects of XR-2 and NMDi. This study identified a combination treatment of NMDi and XR-2 which could serve as a novel cancer therapeutic approach for MDM2-overexpressed TP53 wild-type cancers and delineated a future therapy based on the further reactivation of p53.