Pharmacological inhibition of WIP1 sensitizes acute myeloid leukemia cells to MDM2 inhibitor Nutlin-3a

The wild-type p53-inducible protein phosphatase WIP1, encoded by the PPM1D gene, is a negative regulator of p53 and is involved in cell cycle control and DNA damage stress-response. In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in a number of combination strategies. We investigated the therapeutic potential of its inhibition through the selective WIP1 inhibitor (WIP1i) GSK2830371, in association with the MDM2 inhibitor Nutlin-3a (Nut-3a) in a panel of AML cell lines and performed gene expression analysis of single agent and combined treatments. A p53-related signature was significantly upregulated in the TP53-wildtype MV-4-11 AML cell line. Moreover, drug-specific transcriptional changes likely contribute to the synergistic combination effect. TP53-wildtype MV-4-11 and TP53-mutated NOMO-1 cells treated with Nutlin-3a or GSK2830371, or the drug combination (or vehicle) for 16h were used for RNA extraction and hybridization on microarrays.