Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer research : MCR	13	8	2015 Aug	1197-205	Mol Cancer Res

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
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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 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 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 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

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