Journal article
Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma
The Journal of clinical investigation, Vol.128(7), pp.2877-2893
07/02/2018
DOI: 10.1172/JCI98765
PMCID: PMC6026005
PMID: 29863498
Abstract
Drug resistance remains the key problem in cancer treatment. It is now accepted that each myeloma patient harbors multiple subclones and subclone dominance may change over time. The coexistence of multiple subclones with high or low chromosomal instability (CIN) signature causes heterogeneity and drug resistance with consequent disease relapse. In this study, using a tandem affinity purification–mass spectrometry (TAP-MS) technique, we found that NEK2, a CIN gene, was bound to the deubiquitinase USP7. Binding to USP7 prevented NEK2 ubiquitination resulting in NEK2 stabilization. Increased NEK2 kinase levels activated the canonical NF-κB signaling pathway through the PP1α/AKT axis. Newly diagnosed myeloma patients with activated NF-κB signaling through increased NEK2 activity had poorer event-free and overall survivals based on multiple independent clinical cohorts. We also found that NEK2 activated heparanase, a secreted enzyme, responsible for bone destruction in an NF-κB–dependent manner. Intriguingly, both NEK2 and USP7 inhibitors showed great efficacy in inhibiting myeloma cell growth and overcoming NEK2-induced and -acquired drug resistance in xenograft myeloma mouse models.
Details
- Title: Subtitle
- Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma
- Creators
- Reinaldo Franqui-Machin - Molecular Medicine Program andMu Hao - Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAHua Bai - Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAZhimin Gu - Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAXin Zhan - University of IowaHasem Habelhah - Molecular Medicine Program andYogesh Jethava - Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USALugui Qiu - State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, ChinaIvana Frech - Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAGuido Tricot - Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAFenghuang Zhan - Molecular Medicine Program and
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.128(7), pp.2877-2893
- DOI
- 10.1172/JCI98765
- PMID
- 29863498
- PMCID
- PMC6026005
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation
- Grant note
- 6094-12 / ; R01CA152105 / ;
- Language
- English
- Date published
- 07/02/2018
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Surgery; Internal Medicine
- Record Identifier
- 9984047656502771
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