Abstract
<div>Abstract<p><b>Purpose:</b> MDM2 is a key negative regulator of the p53 signaling pathway. We aimed to evaluate the inter-relationships between <i>MDM2 SNP309</i>, mRNA expression, amplification, and <i>TP53</i> 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.</p><p><b>Experimental Design:</b> <i>SNP309</i> was genotyped in the NCI-60 cancer cell lines. <i>MDM2</i> mRNA levels and gene copy number were measured using real-time PCR. We assessed the inter-relationship between <i>MDM2</i> genetic alterations, <i>TP53</i> mutations, and the cytotoxicity of two MDM2 inhibitors (RITA and Nutlin-3) as well as 111 other drugs with known mechanisms of action.</p><p><b>Results:</b> In the overall NCI-60 cell panel, <i>MDM2</i> mRNA levels were not associated with <i>SNP309</i> but with increased gene copy number. However, <i>SNP309</i> strongly determined the <i>MDM2</i> mRNA expression in cancer cells with wild-type <i>TP53</i>. Cancer cells with wild-type <i>TP53</i> also had significantly higher <i>MDM2</i> copies. In the overall panel, <i>MDM2</i> copy number was independently correlated with increased sensitivity to commonly used alkylating agents and topoisomerase I and II inhibitors. <i>SNP309</i> was significantly associated with increased sensitivity to alkylating agents and topoisomerase I inhibitors in the cells with wild-type <i>TP53</i>. In addition, <i>TP53</i> mutations were the only factor significantly associated with cellular resistance to the MDM2 inhibitor RITA.</p><p><b>Conclusions:</b> Our results suggest that <i>MDM2</i> copy number and <i>SNP309</i> 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)</p></div>
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