Abstract 1780: Targeted inactivation of CRL4-CDT2 E3 ubiquitin ligase as a novel therapeutic strategy for malignant melanoma

The CRL4 CDT2 E3 ubiquitin ligase is emerging as a critical regulator cell cycle progression, primarily through the targeted ubiquitylation and degradation of critical cell cycle regulators including CDT1, p21 and SET8 via the 26S proteasome. CDT2, the substrate receptor of the CRL4 CDT2 E3 ligase is overexpressed or amplified in several human malignancies, but its role in the development or progression of these cancers remains elusive. We show that CDT2 is overexpressed in primary and metastatic melanoma. Targeted depletion of CDT2 by si-RNA or its pharmacological inhibition by MLN4924, a selective NEDD8-activating enzyme (NAE) inhibitor, suppressed the proliferation of melanoma cancer cells in vitro and inhibited tumor growth of human melanoma xenografts in mice, irrespective of the BRAF mutation status. Inhibition of CRL4 CDT2 in melanoma cells with various genetic backgrounds, but not in immortalized human melanocytes, resulted in robust p21- and SET8-dependent rereplication. These results identify the CRL4 CDT2 E3 ubiquitin ligase as a promising new therapeutic target for cutaneous melanoma, and demonstrate the efficacy of MLN4924 as a promising anti-melanoma agent. Citation Format: Mouadh Benamar, Fadila Guessous, Patrick Corbett, Craig L. Slingluff, Tarek Abbas. Targeted inactivation of CRL4-CDT2 E3 ubiquitin ligase as a novel therapeutic strategy for malignant melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1780. doi:10.1158/1538-7445.AM2015-1780