title: Recent advances and future directions in targeting the secretory apparatus in multiple myeloma.
abstract: Multiple myeloma is a genetically heterogeneous tumour of transformed plasma cells, terminally differentiated effectors of the B cell lineage specialized in producing large amounts of immunoglobulins. The uniquely well-developed secretory apparatus that equips normal and transformed plasma cells with the capacity for high-level protein secretion constitutes a distinctive therapeutic target. In this review we discuss how fundamental cellular processes, such as the unfolded protein response (UPR), endoplasmic reticulum (ER)-associated degradation and autophagy, maintain intracellular protein homeostasis (proteostasis) and regulate plasma cell ontogeny and malignancy. We summarize our current understanding of the cellular effects of proteasome inhibitors and the molecular bases of resistance to them. Furthermore, we discuss how improvements in our understanding of the secretory apparatus and of the complex interactions between intracellular protein synthesis and degradation pathways can disclose novel drug targets for multiple myeloma, defining a paradigm of general interest for cancer biology and disorders of altered proteostasis.
authors.affiliation: Department of Medicine, Centre for Haematology, Imperial College London, London, UK.
authors.forename: Holger W
authors.initials: HW
authors.lastname: Auner
authors.forename: Simone
authors.initials: S
authors.lastname: Cenci
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001343:Autophagy; D019008:Drug Resistance, Neoplasm; D060746:Endoplasmic Reticulum-Associated Degradation; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy*; D010950:Plasma Cells / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D059748:Proteolysis; D055571:Secretory Pathway / Q000187:drug effects*; D056811:Unfolded Protein Response
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors
keywords: endoplasmic reticulum; endoplasmic reticulum-associated degradation; multiple myeloma; proteasome; unfolded protein response