期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：46
页码：13162-13167
DOI：10.1073/pnas.1608067113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceProteasome inhibitors show remarkable anti-multiple myeloma (MM) activity in preclinical and clinical studies. However, resistance develops in the majority of patients, and novel treatments are urgently needed. Histone deacetylase 6 (HDAC6) has been shown to mediate aggresomal protein degradation and could be a potential target for combination treatment to overcome drug resistance. Here we designed and developed an HDAC6-selective small molecule inhibitor, WT161, and used this compound to define mechanisms of anti-MM activity, both alone and in combination with proteasome inhibitors in in vitro and in vivo studies. This study has established the framework for combination treatment of HDAC6 inhibitors with proteasome inhibitors in MM and validates an in vivo quality chemical probe for broad use by the research community. Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways of protein homeostasis. Blockade of proteasomal degradation of polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads to drug-resistant relapse in most patients. In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown of polyubiquitinated misfolded proteins with the histone deacetylase 6 (HDAC6) inhibitor tubacin enhances BTZ-induced cytotoxicity in MM cells in vitro. However, these foundational studies were limited by the pharmacologic liabilities of tubacin as a chemical probe with only in vitro utility. Emerging from a focused library synthesis, a potent, selective, and bioavailable HDAC6 inhibitor, WT161, was created to study the mechanism of action of HDAC6 inhibition in MM alone and in combination with BTZ. WT161 in combination with BTZ triggers significant accumulation of polyubiquitinated proteins and cell stress, followed by caspase activation and apoptosis. More importantly, this combination treatment was effective in BTZ-resistant cells and in the presence of bone marrow stromal cells, which have been shown to mediate MM cell drug resistance. The activity of WT161 was confirmed in our human MM cell xenograft mouse model and established the framework for clinical trials of the combination treatment to improve patient outcomes in MM.
