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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 ?-subunits. Additionally, we explore potential strategies to overcome PI resistance.

SUBMITTER: Kale AJ

PROVIDER: S-EPMC3521846 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Molecular mechanisms of acquired proteasome inhibitor resistance.

Kale Andrew J AJ Moore Bradley S BS

Journal of medicinal chemistry 20121003 23

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 acquire ...[more]

PMID: 22978849

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