Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells.

Tatsuya Kawase,Yoko Ueno,Yasushi Amano,Taisuke Nakazawa,Masamichi Mori,Taku Yoshida,Tomoyuki Suzuki,Tomohiro Eguchi,Hirofumi Tsuzuki

doi:10.18632/oncotarget.27222

Tatsuya Kawase, Yoko Ueno + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.27222

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Journal: Oncotarget	Publication Date: Oct 22, 2019
Citations: 43	License type: cc-by

Affiliation: Astellas Pharma (Japan)

Abstract

Therapeutic effects of FLT3 inhibitors have been reported in acute myeloid leukemia (AML) with constitutively activating FLT3 mutations, including internal tandem duplication (ITD) and point mutation, which are found in approximately one-third of AML patients. One of the critical issues of treatment with FLT3 inhibitors in FLT3-mutated AML is drug resistance. FLT3 ligand (FL) represents a mechanism of resistance to FLT3 inhibitors, including quizartinib, midostaurin, and sorafenib, in AML cells harboring both wild-type and mutant FLT3 (FLT3wt/FLT3mut). Here, we investigated the effect of FL on the efficacy of gilteritinib, a FLT3 inhibitor, in AML-derived cells in vitro and in mice. In contrast to other FLT3 inhibitors, FL stimulation had little effect on growth inhibition or apoptosis induction by gilteritinib. The antitumor activity of gilteritinib was also comparable between xenograft mouse models injected with FL-expressing and mock MOLM-13 cells. In the FLT3 signaling analyses, gilteritinib inhibited FLT3wt and FLT3-ITD to a similar degree in HEK293 and Ba/F3 cells, and similarly suppressed FLT3 downstream signaling molecules (including ERK1/2 and STAT5) in both the presence and absence of FL in MOLM-13 cells. Co-crystal structure analysis showed that gilteritinib bound to the ATP-binding pocket of FLT3. These results suggest that gilteritinib has therapeutic potential in FLT3-mutated AML patients with FL overexpression.

Highlights

Fms-like tyrosine kinase 3 (FLT3) is a member of the class III family of receptor tyrosine kinases expressed on early hematopoietic stem and progenitor cells, and plays an important role in hematopoiesis [1]
Consistent with previous reports, our findings demonstrate that the growth inhibitory effects of quizartinib and midostaurin on MOLM-13 cells were attenuated in the presence compared with the absence of FLT3 ligand (FL)
The inhibitory effects of quizartinib and midostaurin on the growth of MV4-11 cells were comparable between the presence and absence of FL (Figure 1C and 1D). These results indicate that unlike quizartinib and midostaurin, FL had no effect on the growth inhibitory effect of gilteritinib in acute myeloid leukemia (AML) cells with FLT3wt/FLT3-internal tandem duplication (ITD)

Summary

Introduction

Fms-like tyrosine kinase 3 (FLT3) is a member of the class III family of receptor tyrosine kinases expressed on early hematopoietic stem and progenitor cells, and plays an important role in hematopoiesis [1]. Mutations at the JMD or TKD of FLT3 induce constitutive kinase activation that is independent of FL, and occurs in approximately one-third of acute myeloid leukemia (AML) patients [4, 5]. Activating point mutations in the TKD are observed in patients with AML, but at a lower frequency than ITD mutations [5, 8]. These activating mutations are oncogenic and render a state of “oncogene addiction” in this disease [5, 9,10,11]. FLT3 is considered a promising drug target in AML patients with FLT3 mutations

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