Journal
ONCOTARGET
Volume 8, Issue 57, Pages 97516-97527Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.22178
Keywords
STAT3 mutation; Hsp90 and JAK inhibitors; high-throughput compound screening; hematological malignancy
Categories
Funding
- Orion Research Foundation
- Sigrid Juselius Foundation
- TEKES - the Finnish Funding Agency for Technology and Innovation
- Academy of Finland
- State funding for university-level health research in Finland
- European Research Council (M-IMM)
- Instrumentarium Science Foundation
- Emil Aaltonen Foundation
- Finnish Cancer Institute
- Finnish Cancer Organizations
- Finnish Hematology Association
Ask authors/readers for more resources
Constitutive JAK/STAT3 signaling contributes to disease progression in many lymphoproliferative disorders. Recent genetic analyses have revealed gain-of-function STAT3 mutations in lymphoid cancers leading to hyperactivation of STAT3, which may represent a potential therapeutic target. Using a functional reporter assay, we screened 306 compounds with selective activity against various target molecules to identify drugs capable of inhibiting the cellular activity of STAT3. Top hits were further validated with additional models including STAT3-mutated natural killer (NK)-cell leukemia/lymphoma cell lines and primary large granular lymphocytic (LGL) leukemia cells to assess their ability to inhibit STAT3 phosphorylation and STAT3 dependent cell viability. We identified JAK, mTOR, Hsp90 and CDK inhibitors as potent inhibitors of both WT and mutant STAT3 activity. The Hsp90 inhibitor luminespib was highly effective at reducing the viability of mutant STAT3 NK cell lines and LGL leukemia patient samples. Luminespib decreased the phosphorylation of mutant STAT3 at Y705, whereas JAK1/JAK2 inhibitor ruxolitinib had reduced efficacy on mutant STAT3 phosphorylation. Additionally, combinations involving Hsp90, JAK and mTOR inhibitors were more effective at reducing cell viability than single agents. Our findings show alternative approaches to inhibit STAT3 activity and suggest Hsp90 as a therapeutic target in lymphoproliferative disorders with constitutively active STAT3.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available