Journal
EBIOMEDICINE
Volume 24, Issue -, Pages 43-55Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2017.09.016
Keywords
DNA damage; Replication stress; Mitotic inhibitor; MDM2 antagonist; Melanoma; Polyploidy; p21; p53
Funding
- Department of Veterans Affairs [5101BX000196-04]
- NIH [CA116021, CA116021-S1, K23 CA204726, GM084333]
- Senior Research Career Scientist Award
- Vanderbilt Clinical Oncology Career Development program funded through NIH K12 [CA90625]
- Vanderbilt Ingram Cancer Center [P30 CA68485]
- Harry J. Lloyd Charitable Trust award [019720-001]
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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. (C) 2017 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.
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