Novel AXL-targeted agents overcome FLT3 inhibitor resistance in FLT3-ITD+ acute myeloid leukemia cells

被引：7
|
作者：
Liu, Yi [1 ,2 ]
Wei, Jing [2 ]
Liu, Jiaxin [2 ]
Ma, Weina [2 ]
Duan, Yanting [3 ,4 ]
Liu, Daihong [1 ,5 ]
机构：
[1] Chinese PLA Med Sch, Dept Hematol, 28 Fuxing Rd, Beijing 100853, Peoples R China
[2] Peoples Liberat Army Gen Hosp, Med Ctr 6, Dept Hematol, Beijing 100048, Peoples R China
[3] Beijing Inst Pharmacol & Toxicol, State Key Lab Toxicol & Med Countermeasures, 27 Taiping Rd, Beijing 100850, Peoples R China
[4] Beijing Inst Pharmacol & Toxicol, Beijing Key Lab Therapeut Gene Engn Antibody, Beijing 100850, Peoples R China
[5] Chinese Peoples Liberat Army Gen Hosp, Dept Hematol, Beijing 100853, Peoples R China
来源：
ONCOLOGY LETTERS | 2021年 / 21卷 / 05期
关键词：
anti-AXL receptor tyrosine kinase antibody; AXL receptor tyrosine kinase small-molecule inhibitor; acute myeloid leukemia; FLT3; mutations; synergistic cytotoxic effect; drug resistance;
D O I：
10.3892/ol.2021.12658
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
AXL receptor tyrosine kinase (AXL) upregulation mediates drug resistance in several types of human cancer and has become a therapeutic target worthy of exploration. The present study investigated AXL antigen expression and the effects of novel AXL-targeted agents in acute myeloid leukemia (AML) cells. AXL antigen expression in drug-sensitive and drug-resistant human AML cell lines, and AML blast cells from 57 patients with different clinical characteristics, was analyzed by flow cytometry and compared. Furthermore, the effects of the novel AXL antibody DAXL-88, antibody-drug conjugate DAXL-88-monomethyl auristatin E (MMAE), AXL small molecule inhibitor R428 and their combination with FMS-like tyrosine kinase 3 (FLT3) inhibitor quizartinib (AC220) in AML cells were analyzed by Cell Counting Kit-8 assay, flow cytometry and western blotting. The present study revealed that AXL antigen expression was upregulated in FLT3-internal tandem duplication (ITD)/tyrosine kinase domain mutation-positive (TKD)(+) AML blast cells compared with FLT3-ITD/TKD- AML cells. Additionally, AXL antigen expression was markedly upregulated in the AC220-resistant FLT3-ITD+ MV4-11 cell line (MV4-11/AC220) and in FLT3 inhibitor-resistant blast cells from a patient with FLT3-ITD+ AML compared with parental sensitive cells. The AXL-targeted agents DAXL-88, DAXL-88-MMAE and R428 exhibited dose-dependent cytotoxic effects on FLT3-mutant AML cell lines (THP-1, MV4-11 and MV4-11/AC220) and blast cells from patients with FLT3-ITD+ AML. Combinations of AXL-targeted agents with AC220 exerted synergistic cytotoxic effects and induced apoptosis in MV4-11/AC220 cells and FLT3 inhibitor-resistant blast cells. The antileukemic effect of DAXL-88 and DAXL-88-MMAE may rely on their ability to block AXL, FLT3 and their downstream signaling pathways. The present study demonstrated the association between AXL antigen expression upregulation and drug resistance in FLT3-ITD+ AML, and proposed a method for overcoming FLT3 inhibitor resistance of FLT3-ITD+ AML using novel AXL-targeted agents.
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页数：10
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