Peficitinib suppresses diffuse-type tenosynovial giant cell tumor by targeting TYK2 and JAK/STAT signaling

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Diffuse-type tenosynovial giant cell tumor (dTGCT) is a rare, destructive neoplastic proliferation of the synovium.
• Current surgical treatment for dTGCT has a high recurrence rate (up to 50%), necessitating novel therapeutic strategies.
• The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is implicated in rheumatoid arthritis (RA) and its role in dTGCT is unexplored.

Purpose of the Study:

• To investigate the role of JAK/STAT signaling in dTGCT pathogenesis.
• To screen clinically approved JAK inhibitors for potential dTGCT treatment.
• To identify a more effective therapeutic agent than the current FDA-approved drug, pexidartinib.

Main Methods:

• Fibroblast-like synoviocytes (FLS) and macrophages were isolated from 10 dTGCT patient synovial tissues.
• Five clinically approved JAK inhibitors were screened for efficacy against dTGCT cells in 2-D and 3-D cultures.
• Cell viability, death, inflammation, and JAK family member activity were assessed.

Main Results:

• JAK/STAT signaling was found to be significantly activated in dTGCT synovium, similar to RA.
• Peficitinib demonstrated the highest potency among the tested JAK inhibitors in mitigating dTGCT FLS and macrophage pathological responses.
• Peficitinib's efficacy significantly surpassed that of pexidartinib, the sole FDA-approved drug for dTGCT.

Conclusions:

• JAK/STAT signaling, especially involving tyrosine kinase 2 (TYK2), is a key mechanism in dTGCT.
• Peficitinib effectively inhibits key pathological pathways in dTGCT FLS and macrophages.
• Peficitinib represents a promising therapeutic candidate for dTGCT, potentially offering superior efficacy to existing treatments.