When Cancer Fights Back: Multiple Myeloma, Proteasome Inhibition, and the Heat-Shock Response

• Type of Material: Article
• Authors: Shardule P. Shah, Emory University; Sagar Lonial, Emory University; Lawrence Boise, Emory University
• Language: English
• Date: 2015-08-01
• Publisher: American Association for Cancer Research
• Publication Version: Final Published Version
• Copyright Statement: © 2015 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1541-7786.MCR-15-0135
• Title of Journal or Parent Work: Molecular Cancer Research
• ISSN: 1541-7786
• Volume: 13
• Issue: 8
• Start Page: 1163
• End Page: 1173
• Grant/Funding Information: Support provided by P30 CA138292 and The TJ Martell Foundation.; LHB is a Georgia Cancer Coalition Distinguished Cancer Scientist.
• Keywords: GENE-EXPRESSION; MOLECULAR-MECHANISMS; Science & Technology; Life Sciences & Biomedicine; NF-KAPPA-B; ANTICANCER STRATEGY; UNFOLDED PROTEIN RESPONSE; PROTEOTOXIC STRESS; Cell Biology; FACTOR-I; Oncology; HSP90 INHIBITOR; CELL-LINES; TRANSCRIPTION FACTOR HSF1
• Research Categories: Biology, Cell; Health Sciences, Oncology; Health Sciences, General

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 heatshock 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.