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Ref Type Journal Article
PMID (25964101)
Authors Carrillo AM, Hicks M, Khabele D, Eischen CM
Title Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells.
Journal Molecular cancer research : MCR
Vol 13
Issue 8
Date 2015 Aug
URL
Abstract Text The Mdm2 oncogene is a negative regulator of the p53 tumor suppressor and recently identified inhibitor of DNA break repair. Nutlin-3 is a small-molecule inhibitor of Mdm2-p53 interaction that can induce apoptosis in cancer cells through activation of p53. Although this is a promising therapy for those cancers with wild-type p53, half of all human cancers have inactivated p53. Here, we reveal that a previously unappreciated effect of Nutlin is inhibition of DNA break repair, stemming from its ability to increase Mdm2 protein levels. The Nutlin-induced increase in Mdm2 inhibited DNA double-strand break repair and prolonged DNA damage response signaling independent of p53. Mechanistically, this effect of Nutlin required Mdm2 and acted through Nbs1 of the Mre11-Rad50-Nbs1 DNA repair complex. In ovarian cancer cells, where >90% have inactivated p53, Nutlin combined with the genotoxic agents, cisplatin or etoposide, had a cooperative lethal effect resulting in increased DNA damage and apoptosis. Therefore, these data demonstrate an unexpected consequence of pharmacologically increasing Mdm2 levels that when used in combination with genotoxic agents induces synthetic lethality in ovarian cancer cells, and likely other malignant cell types, that have inactivated p53.Data reveal a therapeutically beneficial effect of pharmacologically increasing Mdm2 levels combined with chemotherapeutic agents for malignancies that have lost functional p53.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 del ovarian cancer no benefit Nutlin-3a Preclinical Actionable In a preclinical study, treatment with Nutlin-3 had little effect on growth of ovarian cancer cells with deletion of TP53 in culture (PMID: 25964101). 25964101
TP53 inact mut ovarian cancer sensitive Cisplatin + Nutlin-3a Preclinical Actionable In a preclinical study, Nutlin-3 and cisplatin worked cooperatively to induce apoptosis in ovarian cancer cell lines with TP53 inactivating mutations in culture (PMID: 25964101). 25964101
TP53 del ovarian cancer sensitive Cisplatin + Nutlin-3a Preclinical Actionable In a preclinical study, Nutlin-3 and cisplatin worked cooperatively to induce apoptosis and decrease growth of ovarian cancer cells with TP53 deletion in culture (PMID: 25964101). 25964101
TP53 mutant ovarian cancer no benefit Nutlin-3a Preclinical Actionable In a preclinical study, treatment with Nutlin-3 had little effect on growth of ovarian cancer cells with TP53 mutations in culture (PMID: 25964101). 25964101
TP53 mutant ovarian cancer sensitive Etoposide + Nutlin-3a Preclinical Actionable In a preclinical study, Nutlin-3 and etoposide worked cooperatively to induce apoptosis in ovarian cancer cell lines with TP53 inactivating mutations in culture (PMID: 25964101). 25964101
TP53 del ovarian cancer sensitive Etoposide + Nutlin-3a Preclinical Actionable In a preclinical study, Nutlin-3 and etoposide worked cooperatively to induce apoptosis and decrease growth of ovarian cancer cells with TP53 deletion in culture (PMID: 25964101). 25964101