Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 6

Tyrosine Kinase Pathways in Rheumatoid Arthritis

William H. Robinson, M.D., Ph.D.
Assistant Professor of Medicine
Stanford University School of Medicine

Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of RA. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr-Abl expressing leukemias, and subsequently found to treat c-Kit expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-alpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. Our studies include fibroblast-like synoviocytes (FLS) and synovial fluid mononuclear cells (SFMCs) derived from human RA patients in which imatinib attenuated FLS PDGFR signaling and SFMC TNF-alpha production. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses provides a powerful approach to treat RA and other inflammatory diseases.

Up to Top