Drug sensitivity profiling identifies potential therapies for lymphoproliferative disorders with overactive JAK/STAT3 signaling

Show full item record



Permalink

http://hdl.handle.net/10138/231544

Citation

Kuusanmäki , H , Dufva , O , Parri , E , van Adrichem , A J , Rajala , H , Majumder , M M , Yadav , B , Parsons , A , Chan , W C , Wennerberg , K , Mustjoki , S & Heckman , C A 2017 , ' Drug sensitivity profiling identifies potential therapies for lymphoproliferative disorders with overactive JAK/STAT3 signaling ' , Oncotarget , vol. 8 , no. 57 , pp. 97516-97527 . https://doi.org/10.18632/oncotarget.22178

Title: Drug sensitivity profiling identifies potential therapies for lymphoproliferative disorders with overactive JAK/STAT3 signaling
Author: Kuusanmäki, Heikki; Dufva, Olli; Parri, Elina; van Adrichem, Arjan J.; Rajala, Hanna; Majumder, Muntasir M.; Yadav, Bhagwan; Parsons, Alun; Chan, Wing C.; Wennerberg, Krister; Mustjoki, Satu; Heckman, Caroline A.
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Clinicum
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Clinicum
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Krister Wennerberg / Principal Investigator
University of Helsinki, Medicum
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2017-11-14
Language: eng
Number of pages: 12
Belongs to series: Oncotarget
ISSN: 1949-2553
URI: http://hdl.handle.net/10138/231544
Abstract: 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.
Subject: STAT3 mutation
Hsp90 and JAK inhibitors
high-throughput compound screening
hematological malignancy
GRANULAR LYMPHOCYTIC-LEUKEMIA
EPSTEIN-BARR-VIRUS
STAT3 MUTATIONS
SERINE PHOSPHORYLATION
MAXIMAL ACTIVATION
MCL-1 EXPRESSION
CELL LYMPHOMAS
SMALL-MOLECULE
INHIBITOR
TARGET
3122 Cancers
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
22178_314306_4_PB.pdf 4.149Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record