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MDM2 Antagonists Counteract Drug-Induced DNA Damage
Anna E Vilgelm1, Priscilla Cobb1, Kiran Malikayil2
1Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, United States; Vanderbilt University School of Medicine, Department of Cancer Biology, Nashville, TN, United States.
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.
Insights
MDM2-p53 antagonists protect melanoma cells from DNA damage caused by anti-cancer drugs. Targeting p21 enhances combination therapy efficacy, offering new strategies for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Antagonists targeting the MDM2-p53 interaction are investigated as anti-cancer agents, particularly for p53-wildtype cancers like melanoma.
- These drugs aim to restore p53 tumor suppressor function.
Purpose of the Study:
- To investigate the protective effects of MDM2-p53 antagonists against DNA damage induced by various anti-cancer drugs in melanoma.
- To elucidate the role of p21 in mediating the response to MDM2-p53 antagonists and combination therapies.
Main Methods:
- Melanoma cells and patient-derived xenografts were treated with MDM2-p53 antagonists and DNA-damaging agents (mitotic kinase inhibitors, chemotherapy).
- Replicative stress, DNA damage, and polyploidy were assessed.
- p53-dependent p21 activation and its role in DNA replication inhibition were analyzed.
- p21 knockout models were used to evaluate drug-induced DNA damage and therapeutic efficacy.
Main Results:
- MDM2-p53 antagonists protected melanoma cells and xenografts from drug-induced DNA damage.
- Mitotic kinase inhibitors induced DNA re-replication and polyploidy, leading to replicative stress and DNA damage.
- MDM2-p53 antagonists mitigated replicative stress by inducing p53-dependent p21 expression, which inhibited DNA replication.
- Loss of p21 exacerbated drug-induced DNA damage and enhanced the anti-tumor effects of combined MDM2 antagonist and mitotic kinase inhibitor therapy in mice.
Conclusions:
- MDM2-p53 antagonists can reduce the DNA damaging effects of certain anti-cancer drugs when co-administered.
- Targeting p21 presents a strategy to enhance the efficacy of combination therapies involving MDM2 antagonists and DNA-damaging agents in melanoma.