Molecular basis of resistance to proteasome inhibitors in hematological malignancies
作者:Denise Niewerth, Gerrit Jansen, Yehuda G. Assaraf , Sonja Zweegman, Gertjan J.L. Kaspers , Jacqueline Cloos
摘要:Over the past decade, the proteasome inhibitor bortezomib (Velcade) has not only gained a cornerstone
position in the treatment of hematological malignancies, particularly multiple myeloma and mantle cell
lymphoma, but also in experimental therapeutics of acute leukemia. However, the therapeutic efficacy of
bortezomib is hampered by the emergence of acquired resistance, for which multifactorial mechanisms
have been identified. This review summarizes the current status ofthe molecular mechanisms underlying
resistance to proteasome inhibitors that emerged in preclinical therapeutic studies, and discusses these
findings in the clinical perspective of novel therapeutic modalities of hematological malignancies. The
specific topics that will be addressed in the current review include the recently established mechanisms of
resistance to proteasome inhibitors: the role of constitutive and immunoproteasomes, mutations in pro-
teasome subunits, unfolded protein response, XBP1 and MARCKS proteins, multidrug efflux transporters,
aggresomes and autophagy, as well as the impact of pro-survival signaling pathways and bone mar-
row microenvironment. The growing knowledge of the determinants that confer bortezomib resistance
and/or toxicity has provided the basis for the rational development of second generation proteasome
inhibitors, some of which were recently approved or that are undergoing clinical evaluation as novel
strategies to overcome bortezomib resistance as well as to enhance clinical therapeutic efficacy along
with minimal side effects. Collectively, these combined approaches should enhance therapeutic efficacy
and outcome in patients with hematological malignancies.
关键词:Bortezomib ,Leukemia ,Multiple myeloma ,Proteasome inhibitor, Resistance
论文方向:[{"id":918,"name":"药物学"}]
发表期刊:
数字识别码:25670156
是否作者本人: 否
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