Activation of inflammasomes by tyrosine kinase inhibitors of vascular endothelial growth factor receptor: Implications for VEGFR TKIs-induced immune related adverse events

Vascular endothelial growth factor (VEGF) promotes tumor angiogenesis through stimulating the proliferation and survival of endothelial cells. The severe adverse events caused by VEGF inhibitors might include immune-related ones; however, details of the mechanism have not been elucidated. We tested whether axitinib, pazopanib, sorafenib, and sunitinib, which are tyrosine kinase inhibitors (TKIs) of VEGF receptor used for the therapy of renal cell carcinoma can activate inflammasomes in differentiated THP-1 cells, a human macrophage cell line. We also performed similar studies with semaxanib. In this study, semaxanib and sorafenib activated the inflammasome of differentiated THP-1 cells. Although pazopanib increased the production of IL-1β, inflammasomes were not activated because Caspase-1 was not activated in differentiated THP-1 cells. Our results support the hypothesis that activation of inflammasomes contributes to the idiosyncratic reactions associated with semaxanib and sorafenib. Although pazopanib did not activate inflammasomes, it did cause increased IL-1β production, which may facilitate the induction of idiosyncratic reactions.