Year: 2017
Type: article
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.
Source: EBioMedicine
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,780
Awards: G1300984159, G1621550296, G283432789, G3433274139, G359867969, G3828336601, G4119117476, G4399516443, G4923790243, G5241415837, G5853943267, G6007454854, G6537411040, G6983782547, G725763919, G8113317439, G818418256, G9000081609, Vanderbilt Clinical Oncology Research Career Development Award, G9000083539, G9000265312, G9000270150, G9000278820, G9000285544, 1/3) MMC, VICC, and TSU: Partners in Eliminating Cancer Disparities
OpenAlex ID: W2756096584