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MDM2 Antagonists Counteract Drug-Induced DNA Damage
- Source :
- EBioMedicine, Vol 24, Iss C, Pp 43-55 (2017)
- Publication Year :
- 2017
- Publisher :
- Elsevier, 2017.
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 23523964
- Volume :
- 24
- Issue :
- C
- Database :
- Directory of Open Access Journals
- Journal :
- EBioMedicine
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.2c72f0bce0994f99b7abe6f544b4d5e2
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.ebiom.2017.09.016