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

Liu,Yi; Wei,Jing; Liu,Jiaxin; Ma,Weina; Duan,Yanting; Liu,Daihong

doi:10.3892/ol.2021.12658

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

Authors:
- Yi Liu
- Jing Wei
- Jiaxin Liu
- Weina Ma
- Yanting Duan
- Daihong Liu
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Affiliations: Department of Hematology, Chinese PLA Medical School, Beijing 100853, P.R. China, Department of Hematology, The Sixth Medical Center of PLA General Hospital, Beijing 100048, P.R. China, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, P.R. China
Published online on: March 18, 2021 https://doi.org/10.3892/ol.2021.12658
Article Number: 397
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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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