Abstract SY18-01: Targeting the p53-MDM2 interaction for cancer therapy

Abstract

Abstract The p53 tumor suppressor is tightly controlled by MDM2 which binds p53 and negatively modulates its transcriptional activity and stability. Many tumors overproduce MDM2 to impair p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may offer a novel approach to cancer therapy. Recently developed potent and selective small-molecule MDM2 antagonists, the nutlins, interact specifically with the p53-binding pocket of MDM2 and release p53 from negative control. Treatment of cancer cells expressing wild-type p53 with nutlins stabilized p53 and activated the p53 pathway. Although half of human tumors retain wild-type p53, the function of the tumor suppressor could be compromised by defective signaling in the pathway. Using nutlin-3a to probe downstream p53 signaling we find that the cell cycle arrest function of p53 is preserved in all tested cancer cell lines expressing wild-type p53 but many have compromised ability to undergo p53-dependent apoptosis. The p53 transcription target and potent CDK inhibitor, p21, has been shown to inhibit the apoptotic response to genotoxic p53 activation. Although it is strongly upregulated by MDM2 antagonists in all tested cancer cell lines, p21 does not affect the apoptotic outcome of nutlin treatment, suggesting that it does not play anti-apoptotic role during non-genotoxic p53 activation. MDM2 controls p53 stability and activity through a feedback mechanism by which both proteins mutually regulate their cellular levels. Nutlins disrupt this regulatory circuit leading to upregulation of both p53 and MDM2. They selectively block the p53-MDM2 interaction but do not affect MDM2 E3 ligase activity that is elevated in the presence of the drug. MDMX, a known p53 inhibitor and MDM2 ubiqutination target decreased with the increase of MDM2, suggesting that MDM2 contributes to antitumor activity of nutlins at least in part by facilitating MDMX degradation. Elevated MDM2 contributes to the apoptotic outcome of nutlin treatment also by interfering with the maturation of subsets of microRNAs. Nutlin-3a doses that shrink xenograft tumors activated p53 signaling in mouse tissues but caused only mild changes in bone marrow, thymus and spleen. These results suggest that p53 activation by MDM2 antagonists may provide an acceptable safety window for cancer therapy. A member of the nutlin family of MDM2 antagonists is currently undergoing Ph I clinical testing in patients with solid and hematological malignancies. Citation Format: Lyubomir T. Vassilev. Targeting the p53-MDM2 interaction for cancer therapy [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY18-01