Molecular Pathways Molecular Pathways: Translational Potential of Deubiquitinases as Drug Targets

The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS coupled with the clinical success of bortezomib for the treatment of multiple myeloma have made the UPS an obvious target for drug development. Deubiquitinases (DUB) are components of the UPS that encompass a diverse family of ubiquitin isopeptidases that catalyze the removal of ubiquitinmoieties from target proteins or from polyubiquitin chains, resulting in altered signaling or changes in protein stability. Increasing evidence has implicated deregulation ofDUB activity in the initiation and progression of cancer. The altered pattern of DUB expression observed inmany tumors can potentially serve as a clinical marker for predicting disease outcome and therapy response. The finding of DUB overexpression in tumor cells suggests that they may serve as novel targets for the development of anticancer therapies. Several specific and broad-spectrum DUB inhibitors are shown to have antitumor activity in preclinical in vivomodels with low levels of systemic toxicity. Future studies will hopefully establish the clinical potential for DUB inhibitors as a strategy to treat cancer. Clin Cancer Res; 20(15); 3908–14. 2014 AACR. Disclosure of Potential Conflicts of Interest S. Linder has ownership interest (including patents) in Vivolux AB. No potential conflicts of interest were disclosed by the other author. CME Staff Planners' Disclosures The members of the planning committee have no real or apparent conflict of interest to disclose.