Shah Shardule P, Lonial Sagar, Boise Lawrence H
Department of Hematology and Medical Oncology, Winship, Cancer Institute of Emory University and the Emory University School of Medicine, Atlanta, Georgia.
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.
Mol Cancer Res. 2015 Aug;13(8):1163-73. doi: 10.1158/1541-7786.MCR-15-0135. Epub 2015 May 26.
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.
多发性骨髓瘤是一种浆细胞恶性肿瘤，2015年在美国估计有26,850例新发病例和11,240例死亡病例。两类主要药物是治疗的支柱——蛋白酶体抑制剂（PI）和免疫调节药物（IMiD）。其他新的靶点正在迅速出现，包括单克隆抗体和组蛋白去乙酰化酶（HDAC）抑制剂。这些治疗选择极大地改善了总体生存率，但目前只有15%至20%的患者实现长期无进展生存或治愈。因此，需要改进治疗选择。改善临床选择的一种潜在方法是针对当前药物的耐药机制。例如，消除保护骨髓瘤细胞免受蛋白酶体抑制的细胞保护热休克反应可能会增强基于PI的疗法。转录因子热休克因子1（HSF1）是热休克反应的主要调节因子。HSF1在蛋白毒性应激反应中至关重要，其激活受翻译后修饰（PTM）控制。本综述详细介绍了HSF1的调节机制，并讨论了利用该调节来增强PI活性。
