Regorafenib and reactive metabolite of sunitinib activate inflammasomes: Implications for multi tyrosine kinase inhibitor-Iiduced immune related adverse events.

Abstract

Multi-targeted tyrosine kinase inhibitors have been developed for the treatment of various cancers, but they are associated with a significant incidence of idiosyncratic drug reactions (IDRs). There is compelling evidence that most IDRs are immune mediated. Activation of inflammasomes is often one of the early steps in the initiation of an immune response. This activation could involve the pharmacological effect of the drug, or it could involve the release of damage associated molecular patters (DAMPs) caused by a reactive metabolite. We tested whether sunitinib, regorafenib, lenvatinib and cabozantinib can directly activate inflammasomes in differentiated THP-1 cells. We found that regorafenib activated the inflammasome of differentiated THP-1 cells directly. We also found that the supernatant from the incubation of sunitinib with FLC-4 cells, which have a high capacity to metabolize drugs, led to activate the inflammasome of differentiated THP-1 cells. In the supernatant of FLC-4 cells with sunitinib, the heat shock protein (HSP) 90 was significantly increased. Sunitinib is known to be oxidized to generate a reactive, potentially toxic quinone imine. These results support the hypothesis that the reactive metabolite of sunitinib can cause the release of DAMPs from hepatocytes, which leads to activation of inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by regorafenib and sunitinib, which in some patients, can cause IDRs.