Modulation Of Mdm2 In Context Of Dna Damage Enhances Cell Death In A Metastatic Breast-To-Lung Xenograft Model

Metastatic breast cancer is highly refractive to current treatment strategies, and new multi-targeted treatments need to be elucidated. In metastatic disease, inhibiting key protein-protein interactions with the murine double minute 2 (MDM2) could be beneficial for developing new treatment modalities since this signaling pathway is a critical regulatory point in cancer progression. Inhibition of protein binding to the hydrophobic pocket of MDM2 by Nutlin-3a can activate pro-apoptotic proteins such p73 and E2F1 as well as decrease pro-angiogenic Hif-1α. Since the DNA damaging agent carboplatin is currently being studied in clinical trials of triple-negative breast cancers (TNBCs), our objective was to evaluate the effects of carboplatin and Nutlin-3a in combination in TNBC in a mutant p53 background. Using a TNBC cell line TMD231 derived from the MDA-MB-231 human breast cancer cell line, we performed combination studies using different ratios of carboplatin to Nutlin-3a in vitro to evaluate the range of carboplatin-mediated DNA damage required to obtain synergism with inhibition of MDM2 function. A fixed ratio of 1:1 carboplatin:Nutlin-3a was strongly synergistic with a combination index of Citation Format: Eva Tonsing-Carter, Harlan E. Shannon, Barbara J. Bailey, Anthony L. Sinn, Kacie M. Peterman, Lindsey D. Mayo, Karen E. Pollok. Modulation of MDM2 in context of DNA damage enhances cell death in a metastatic breast-to-lung xenograft model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1680. doi:10.1158/1538-7445.AM2014-1680