Regorafenib Is Another Potentially Senotherapeutic Tyrosine Kinase Inhibitor
Dasatinib, a tyrosine kinase inhibitor, was one of the first drugs shown to selectively destroy senescent cells and thereby reverse aspects of aging, particularly when used in combination with the plant flavonoid quercetin. Strangely, little attention was given to the question of whether other tyrosine kinase inhibitors can target senescent cells until recently. A number of these compounds have in the past undergone clinical trials, or even been approved for use by regulators, for the treatment of conditions that researchers now suspect to be connected with cellular senescence to a significant degree. Nintedanib, for example, in the context of pulmonary fibrosis, or masitinib in the context of Alzheimer's disease.
In today's open access paper, researchers report on another tyrosine kinase inhibitor that may act to reduce the age-related burden of cellular senescence. It is, as one might expect, an approved cancer drug. The dasatinib and quercetin combination remains one of the more effective senolytic therapies in terms of reducing the burden of senescent cells in animal studies. There is no particular reason as to why dasatinib should be the best in its class, however. It is possible that other tyrosine kinase inhibitors are better, either overall, or for specific use cases. Certainly, by analogy, the class of bcl-2 family inhibitors (including navitoclax, one of the other early senolytic drugs) that selectively destroy senescent cells vary widely in effectiveness.
Senescence, a hallmark of aging, is a factor in age-related diseases (ARDs). Therefore, targeting senescence is widely regarded as a practicable method for modulating the effects of aging and ARDs. Here, we report the identification of regorafenib, an inhibitor of multiple receptor tyrosine kinases, as a senescence-attenuating drug. We identified regorafenib by screening an FDA-approved drug library.
Treatment with regorafenib at a sublethal dose resulted in effective attenuation of the phenotypes of βPIX knockdown-induced and doxorubicin-induced senescence and replicative senescence in IMR-90 cells; cell cycle arrest, and increased SA-β-Gal staining and senescence-associated secretory phenotypes, particularly increasing the secretion of interleukin 6 (IL-6) and IL-8. Consistent with this result, slower progression of βPIX depletion-induced senescence was observed in the lungs of mice after treatment with regorafenib.
Mechanistically, the results of proteomics analysis in diverse types of senescence indicated that growth differentiation factor 15 and plasminogen activator inhibitor-1 are shared targets of regorafenib. Analysis of arrays for phospho-receptors and kinases identified several receptor tyrosine kinases, including platelet-derived growth factor receptor α and discoidin domain receptor 2, as additional targets of regorafenib and revealed AKT/mTOR, ERK/RSK, and JAK/STAT3 signaling as the major effector pathways. Finally, treatment with regorafenib resulted in attenuation of senescence and amelioration of porcine pancreatic elastase-induced emphysema in mice.
Based on these results, regorafenib can be defined as a novel senomorphic drug, suggesting its therapeutic potential in pulmonary emphysema. Senescence is a factor in the pathogenesis of chronic pulmonary diseases, including emphysema. Thus, senotherapy based on senolytics, senomorphics, and their combination has been recognized as a practicable strategy for the treatment of these diseases. Previous studies have reported on the efficacy of regorafenib in animal models of Alzheimer's disease and bleomycin-induced fibrosis. The role of regorafenib in the attenuation of senescence may provide an explanation for its beneficial effects in these disease models.