title: When Cancer Fights Back: Multiple Myeloma, Proteasome Inhibition, and the Heat-Shock Response.
abstract: Multiple myeloma is a plasma cell malignancy with an estimated 26,850 new cases and 11,240 deaths in 2015 in the United States. Two main classes of agents are the mainstays of therapy-proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Other new targets are emerging rapidly, including monoclonal antibodies and histone deacetylase (HDAC) inhibitors. These therapeutic options have greatly improved overall survival, but currently only 15% to 20% of patients experience long-term progression-free survival or are cured. Therefore, improvement in treatment options is needed. One potential means of improving clinical options is to target resistance mechanisms for current agents. For example, eliminating the cytoprotective heat-shock response that protects myeloma cells from proteasome inhibition may enhance PI-based therapies. The transcription factor heat-shock factor 1 (HSF1) is the master regulator of the heat-shock response. HSF1 is vital in the proteotoxic stress response, and its activation is controlled by posttranslational modifications (PTM). This review details the mechanisms of HSF1 regulation and discusses leveraging that regulation to enhance PI activity.
authors.affiliation: Department of Hematology and Medical Oncology, Winship, Cancer Institute of Emory University and the Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Shardule P
authors.initials: SP
authors.lastname: Shah
authors.affiliation: Department of Hematology and Medical Oncology, Winship, Cancer Institute of Emory University and the Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.affiliation: Department of Hematology and Medical Oncology, Winship, Cancer Institute of Emory University and the Emory University School of Medicine, Atlanta, Georgia. Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia. lboise@emory.edu.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000069286:Bortezomib / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D018572:Disease-Free Survival; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism*; D018869:Heat-Shock Response; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry*; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases