Abstract CN05-01: Targeting Mdm2 in DNA repair and chromosome instability.

Abstract

Abstract Mdm2, a direct inhibitor of the p53 tumor suppressor, is frequently overexpressed in many human malignancies. Increased levels of Mdm2 negatively impact genome stability, a common property of cancer cells. Recently, it has been appreciated that both p53-dependent and p53-independent functions of Mdm2 contribute to genome instability and tumorigenesis. Specifically, Mdm2 induces chromosome instability not only by inhibiting p53 activity, but also through inhibition of the Mre11/Rad50/Nbs1 DNA repair complex. We have shown that Mdm2 binds Nbs1 and inhibits early DNA damage signaling, resulting in a delay in DNA break repair. This delay in DNA repair leads to increased chromosome breaks, altered ploidy, and enhanced cellular transformation potential. Elevated Mdm2 levels also increase the severity and frequency of chromosome abnormalities that arise during aging and that have been linked to cancer development. Therefore, Mdm2 negatively influences genome stability, which contributes to tumorigenesis. However, this effect of Mdm2 on the genome may be therapeutically exploitable for the treatment of malignancies. In pursuit of this goal, we have begun testing small molecule inhibitors of Mdm2:p53 interaction, such as Nutlin, for consequences on DNA break repair. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN05-01.