Carfilzomib enhances the suppressive effect of ruxolitinib in myelofibrosis
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
As the first FDA-approved tyrosine kinase inhibitor for treatment of patients with myelofibrosis (MF), ruxolitinib improves clinical symptoms but does not lead to eradication of the disease or significant reduction of the mutated allele burden. The resistance of MF clones against the suppressive action of ruxolitinib may be due to intrinsic or extrinsic mechanisms leading to activity of additional pro-survival genes or signalling pathways that function independently of JAK2/STAT5. To identify alternative therapeutic targets, we applied a pooled-shRNA library targeting ~5000 genes to a JAK2V617F-positive cell line under a variety of conditions, including absence or presence of ruxolitinib and in the presence of a bone marrow microenvironment-like culture medium. We identified several proteasomal gene family members as essential to HEL cell survival. The importance of these genes was validated in MF cells using the proteasomal inhibitor carfilzomib, which also enhanced lethality in combination with ruxolitinib. We also showed that proteasome gene expression is reduced by ruxolitinib in MF CD34+ cells and that additional targeting of proteasomal activity by carfilzomib enhances the inhibitory action of ruxolitinib in vitro. Hence, this study suggests a potential role for proteasome inhibitors in combination with ruxolitinib for management of MF patients.
Date Issued
2021-05-01
Date Acceptance
2021-09-20
Citation
Cancers, 2021, 13 (19)
ISSN
2072-6694
Publisher
MDPI AG
Journal / Book Title
Cancers
Volume
13
Issue
19
Copyright Statement
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/34638347
PII: cancers13194863
Subjects
BORTEZOMIB
carfilzomib
CELLS
INHIBITOR
KAPPA-B
Life Sciences & Biomedicine
myelofibrosis
Oncology
PHOSPHORYLATION
PROTEASOME
PROTEIN
RESISTANCE
ruxolitinib
Science & Technology
shRNA library screen
THERAPY
TUMOR MICROENVIRONMENT
Publication Status
Published
Coverage Spatial
Switzerland
Article Number
4863
Date Publish Online
2021-09-28