Interactions between MDM2 and TP53 Genetic Alterations, and Their Impact on Response to MDM2 Inhibitors and Other Chemotherapeutic Drugs in Cancer Cells

Abstract

PURPOSE: MDM2 is a key negative regulator of the p53 signaling pathway. We aimed to evaluate the inter-relationships between MDM2 SNP309, mRNA expression, amplification, and TP53 mutations, as well as their correlations with responsiveness to MDM2 inhibitors and other commonly used cytotoxic drugs tested in the NCI-60 cancer cell panel. EXPERIMENTAL DESIGN: SNP309 was genotyped in the NCI-60 cancer cell lines. MDM2 mRNA levels and gene copy number were measured using real-time PCR. We assessed the inter-relationship between MDM2 genetic alterations, TP53 mutations, and the cytotoxicity of two MDM2 inhibitors (RITA and Nutlin-3) as well as 111 other drugs with known mechanisms of action. RESULTS: In the overall NCI-60 cell panel, MDM2 mRNA levels were not associated with SNP309 but with increased gene copy number. However, SNP309 strongly determined the MDM2 mRNA expression in cancer cells with wild-type TP53. Cancer cells with wild-type TP53 also had significantly higher MDM2 copies. In the overall panel, MDM2 copy number was independently correlated with increased sensitivity to commonly used alkylating agents and topoisomerase I and II inhibitors. SNP309 was significantly associated with increased sensitivity to alkylating agents and topoisomerase I inhibitors in the cells with wild-type TP53. In addition, TP53 mutations were the only factor significantly associated with cellular resistance to the MDM2 inhibitor RITA. CONCLUSIONS: Our results suggest that MDM2 copy number and SNP309 may predict for response to alkylating agents and topoisomerase inhibitors. These markers should be tested further, particularly in combination with other putative predictive biomarkers. (Clin Cancer Res 2009;15(24):7602-7).