Targeting fibroblast-like synoviocytes with CDK4/6 inhibitors as a novel, non-immunosuppressive treatment strategy for rheumatoid arthritis

Despite advances in rheumatoid arthritis (RA) therapy, a substantial proportion of patients fail to achieve remission with current targeted immunomodulators. The synovial joint and its cells mediate a central role in pathobiology of RA. Within the synovial joint, fibroblast-like synoviocytes (FLSs) are a stromal mesenchymal cell population that have been implicated in the initiation and development of rheumatoid arthritis and may contribute to poor response and treatment resistance. Multiple lines of evidence including genetics, in vitro experiments and animal arthritis model studies implicate the cell-cycle proteins, cyclin dependent kinases (CDKs), CDK4 and CDK6, as key regulators of FLS activity in RA suggesting them as a potential therapeutic target.CDK4/6 inhibition is an established therapeutic strategy in breast cancer, and importantly, translational and clinical data observed in oncology patients demonstrate decreasing aromatase inhibitor-induced arthralgia, or ameliorating symptoms of concomitant RA by treatment with currently approved oncology CDK4/6 inhibitors. However, a narrow therapeutic index paired with the risk of myelosuppression and QT-interval prolongation precludes their use in non-oncology indications such as RA. Therefore, next generation CDK4/6 inhibitors with improved therapeutic index have been designed. A recently published phase 1b study of TCK-276 in RA patients, indicated promising signs of early clinical efficacy and an absence of class-related side effects.This review summarises the molecular biology of CDK4/6, its role in RA pathobiology and discusses how therapeutic CDK4/6 inhibition could form a novel therapeutic class addressing unmet need in the treatment of RA.