rg7388 and Melanoma

Cutaneous melanoma is the most serious skin malignancy and new therapeutic strategies are needed for advanced melanoma. TP53 mutations are rare in cutaneous melanoma and hence activation of wild-type p53 is a potential therapeutic strategy in cutaneous melanoma. Here, we investigated the WIP1 inhibitor, GSK2830371, and MDM2-p53 binding antagonists (nutlin-3, RG7388 and HDM201) alone and in combination treatment in cutaneous melanoma cell lines and explored the mechanistic basis of these responses in relation to the genotype and induced gene expression profile of the cells.. A panel of three p53. GSK2830371, at doses (⩽10 μM) that alone had no growth-inhibitory or cytotoxic effects on the cells, nevertheless significantly potentiated the growth-inhibitory and clonogenic cell killing effects of MDM2 inhibitors in p53. GSK2830371, a WIP1 inhibitor, at doses with no growth-inhibitory activity alone, potentiated the growth-inhibitory and cytotoxic activity of MDM2 inhibitors by increasing phosphorylation, acetylation and stabilisation of p53 in cutaneous melanoma cells in a functional p53-dependent manner.

Topics: Aminopyridines; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dipeptides; Drug Synergism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Melanoma; Melanoma, Cutaneous Malignant; Mutagenesis, Site-Directed; para-Aminobenzoates; Phosphorylation; Piperazines; Protein Binding; Protein Phosphatase 2C; Protein Stability; Proto-Oncogene Proteins c-mdm2; Pyrrolidines; Skin Neoplasms; Tumor Suppressor Protein p53

Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Azepines; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; DNA Damage; DNA Replication; HCT116 Cells; Humans; Imidazoles; Melanoma; Mice; para-Aminobenzoates; Piperazines; Protein Binding; Proto-Oncogene Proteins c-mdm2; Pyrimidines; Pyrrolidines; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays