title: Molecular mechanisms of acquired proteasome inhibitor resistance.
abstract: The development of proteasome inhibitors (PIs) has transformed the treatment of multiple myeloma and mantle cell lymphoma. To date, two PIs have been FDA approved, the boronate peptide bortezomib and, most recently, the epoxyketone peptide carfilzomib. However, intrinsic and acquired resistance to PIs, for which the underlying mechanisms are poorly understood, may limit their efficacy. In this Perspective, we discuss recent advances in the molecular understanding of PI resistance through acquired bortezomib resistance in human cell lines and evolved salinosporamide A (marizomib) resistance in bacteria. Resistance mechanisms discussed include the up-regulation of proteasome subunits and mutations of the catalytic β-subunits. Additionally, we explore potential strategies to overcome PI resistance.
authors.affiliation: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California-San Diego, La Jolla, California 92093, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kale
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Moore
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex