Targeting c-KIT (CD117) by dasatinib and radotinib promotes acute myeloid leukemia cell death

Jeong Yi Kim,Jin Ho Baek,Jae-Cheol Jo,Sook-Kyoung Heo,Hawk Kim,Yunsuk Choi,Sujin Koh,Eui-Kyu Noh,Young Joo Min,Yoo Kyung Jeong

doi:10.1038/s41598-017-15492-5

Abstract

Dasatinib and radotinib are oral BCR-ABL tyrosine kinase inhibitors that were developed as drugs for the treatment of chronic myeloid leukemia. We report here that the c-KIT (CD117) targeting with dasatinib and radotinib promotes acute myeloid leukemia (AML) cell death, and c-KIT endocytosis is essential for triggering c-KIT-positive AML cell death by dasatinib and radotinib during the early stages. In addition, dasatinib and radotinib reduce heat shock protein 90β (HSP90β) expression and release Apaf-1 in c-KIT-positive AML cells. Finally, this activates a caspase-dependent apoptotic pathway in c-KIT-positive AML cells. Moreover, the inhibition of c-KIT endocytosis by dynamin inhibitor (DY) reversed cell viability and c-KIT expression by dasatinib and radotinib. HSP90β expression was recovered by DY in c-KIT-positive AML cells as well. Furthermore, the effect of radotinib on c-KIT and HSP90β showed the same pattern in a xenograft animal model using HEL92.1.7 cells. Therefore, dasatinib and radotinib promote AML cell death by targeting c-KIT. Taken together, these results indicate that dasatinib and radotinib treatment have a potential role in anti-leukemic therapy on c-KIT-positive AML cells.

Highlights

To evaluate the role of c-KIT and HSP90β in AML cell death in vivo, we engrafted HEL92.1.7 cells into nude mice
The protein and mRNA expression of HSP90β were significantly decreased by dasatinib and radotinib in KASUMI-1 and HEL92.1.7 cells, in a time-dependent manner (Supplementary Figs 3 and 5)
We investigated the relationship among the HSP90β, Apaf-1, and c-KIT by co-immunoprecipitation and Western assay (Fig. 6), and the proposed pathways are presented in Supplementary Fig. 6 based on our results

Summary

Introduction

To evaluate the role of c-KIT and HSP90β in AML cell death in vivo, we engrafted HEL92.1.7 cells into nude mice. The results showed that the inhibition of c-KIT and HSP90β by radotinib led to a profound suppression of tumor growth, as evidenced by a significant reduction in tumor volume and weight (Supplementary Fig. 8A–C). The expression of human CD45+c-KIT+ cells, human CD45+HSP90+ cells and human HSP90β mRNA in tumor tissues isolated from the mice were significantly decreased (Supplementary Fig. 8D–F)

Methods

Results

Discussion

Conclusion