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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Constitutive Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling is implicated in lymphoproliferative disorder progression.
• Gain-of-function mutations in STAT3 lead to its hyperactivation, presenting a potential therapeutic target in lymphoid cancers.

Purpose of the Study:

• To screen compounds for STAT3 inhibitory activity.
• To validate potential inhibitors in STAT3-mutated leukemia and lymphoma models.
• To identify novel therapeutic strategies targeting STAT3 in lymphoproliferative disorders.

Main Methods:

• A functional reporter assay screened 306 compounds for STAT3 inhibition.
• Hit compounds were validated in STAT3-mutated natural killer (NK)-cell leukemia/lymphoma and large granular lymphocytic (LGL) leukemia models.
• Inhibition of STAT3 phosphorylation and cell viability was assessed.

Main Results:

• Janus kinase (JAK), mTOR, Heat shock protein 90 (Hsp90), and cyclin-dependent kinase (CDK) inhibitors demonstrated potent inhibition of both wild-type (WT) and mutant STAT3.
• The Hsp90 inhibitor luminespib significantly reduced the viability of mutant STAT3 NK cell lines and LGL leukemia patient samples.
• Luminespib decreased mutant STAT3 phosphorylation at Y705, while ruxolitinib showed less efficacy on mutant STAT3 phosphorylation.

Conclusions:

• Hsp90, JAK, and mTOR inhibitors show promise for targeting constitutively active STAT3 in lymphoproliferative disorders.
• Combination therapies involving these inhibitors may be more effective than single agents.
• Hsp90 inhibition represents a viable therapeutic strategy for lymphoproliferative disorders driven by STAT3 hyperactivation.