Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT and FLT3 in hematologic malignancies : Mutant KIT and FLT3 response to Tyrosine Kinase Inhibitors

Summary

Mutations in two type-3 receptor tyrosine kinases (RTK), KIT and FLT3, are common in both acute myeloid leukemia (AML) and systemic mastocytosis (SM) and lead to hyperactivation of key signaling pathways. Fortunately, a significant number of tyrosine kinase inhibitors TKIs have been developed that target either FLT3 or KIT and significant clinical benefit has been demonstrated in multiple clinical trials. Given the structural similarity of FLT3 and KIT, it is not surprising that some of these TKIs inhibit both of these receptors. This is typified by midostaurin, which has been FDA approved for mutant FLT3-positive AML and for KIT-D816V-positive SM. Here, we compare the in vitro activities of the clinically available FLT3 and KIT inhibitors with those of midostaurin against a panel of cells expressing a variety of oncogenic FLT3 or KIT receptors, including wild-type (wt) FLT3, FLT3-ITD, FLT3-D835Y, the resistance mutant FLT3-ITD+F691L, KIT-D816V, and KIT-N822K. We also examined the effects of these inhibitors in vitro and in vivo on cells expressing mutations in c-CBL found in AML that result in hypersensitization of TK receptors such as FLT3 and KIT. The results show a wide spectrum of activity of these various mutations to these clinically available TKIs.