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MDM2 Antagonists Counteract Drug-Induced DNA Damage.

Vilgelm AE, Cobb P, Malikayil K, Flaherty D, Andrew Johnson C, Raman D, Saleh N, Higgins B, Vara BA, Johnston JN, Johnson DB, Kelley MC, Chen SC, Ayers GD, Richmond A
EBioMedicine. 2017 24: 43-55

PMID: 29030058 · PMCID: PMC5652019 · DOI:10.1016/j.ebiom.2017.09.016

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.

Copyright © 2017. Published by Elsevier B.V.

MeSH Terms (20)

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

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