Drug sensitivity profiling identifies potential therapies for lymphoproliferative disorders with overactive JAK/STAT3 signaling
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Heikki Kuusanmäki1,2, Olli Dufva2, Elina Parri1, Arjan J. van Adrichem1, Hanna Rajala2, Muntasir M. Majumder1, Bhagwan Yadav1, Alun Parsons1, Wing C. Chan3, Krister Wennerberg1, Satu Mustjoki2,4,* and Caroline A. Heckman1,*
1Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
2Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
3Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA
4Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
*These authors have contributed equally to this work
Caroline A. Heckman, email: [email protected]
Satu Mustjoki, email: [email protected]
Keywords: STAT3 mutation; Hsp90 and JAK inhibitors; high-throughput compound screening; hematological malignancy
Received: December 21, 2016 Accepted: August 27, 2017 Published: October 31, 2017
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.
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