Fedratinib and gandotinib induce apoptosis and enhance the efficacy of tyrosine kinase inhibitors in human mast cells.

Abstract

Mastocytosis is characterized by an abnormal accumulation of mast cells (MC) in various organs. In most patients, the disease is driven by the KIT D816V mutation, leading to activation of the KIT receptor and subsequent downstream signaling, including the JAK/STAT pathway. In recent years, KIT-targeting tyrosine kinase inhibitors (TKI) have emerged for the treatment of systemic mastocytosis; however, the overall response rate is often not sufficient. In this study, we investigated whether targeting the JAK/STAT pathway might be a novel treatment approach in mastocytosis. Using human MC lines carrying the KIT D816V mutation and human primary cord blood-derived MC, we examined the effects of different JAK inhibitors. Our findings revealed that the JAK inhibitors fedratinib and gandotinib decreased viability, reduced proliferation, and induced apoptosis in KIT D816V-positive MC lines (HMC-1.2 and ROSA ^{KIT D816V}). In contrast, ruxolitinib, baricitinib, upadacitinib and abrocitinib failed to affect MC functions. Combinatorial treatment with fedratinib, gandotinib and the two TKI avapritinib and midostaurin was more effective than treatment with TKI alone. Fedratinib also induced apoptosis and enhanced the efficacy of TKI in primary cord blood-derived MC. These results indicate that fedratinib and gandotinib, but not the other JAK inhibitors used in this study, can suppress viability and induce apoptosis in KIT D816V-mutant and KIT WT MC and increase effects of TKI. These findings suggest to explore fedratinib and gandotinib as novel treatment option in mastocytosis.