title: Emerging Therapeutic Strategies for Overcoming Proteasome Inhibitor Resistance.
abstract: The debut of the proteasome inhibitor bortezomib (Btz; Velcade®) radically and immediately improved the treatment of multiple myeloma (MM), an incurable malignancy of the plasma cell. Therapeutic resistance is unavoidable, however, and represents a major obstacle to maximizing the clinical potential of the drug. To address this challenge, studies have been conducted to uncover the molecular mechanisms driving Btz resistance and to discover new targeted therapeutic strategies and combinations that restore Btz activity. This review discusses the literature describing molecular adaptations that confer Btz resistance with a primary disease focus on MM. Also discussed are the most recent advances in therapeutic strategies that overcome resistance, approaches that include redox-modulating agents, murine double minute 2 inhibitors, therapeutic monoclonal antibodies, and new epigenetic-targeted drugs like bromodomain and extra terminal domain inhibitors.
authors.affiliation: Department of Cellular and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, USA. Electronic address: dolloffn@musc.edu.
authors.forename: Nathan G
authors.initials: NG
authors.lastname: Dolloff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy; D061988:Proteasome Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D000069286:Bortezomib
keywords: Bortezomib; MDM2; Multiple myeloma; PSMβ5; Proteasome inhibitor; Redox; Resistance; Velcade