Targeting AXL kinase sensitizes leukemic stem and progenitor cells to venetoclax treatment in acute myeloid leukemia
| Autor: | Yubin Ge, Hong Liu, Rick Li, German Novakovskiy, Jun Yan, Depei Wu, Florian Kuchenbauer, Min Chen, Katharina Rothe, Zaihui Zhang, Xiuyan Zhang, Sung-Eun Nam, Yun Zhao, Irina A Maksakova, Xiaojia Niu, Xiaoyan Jiang, Yehyeon Ahn, Arefeh Rouhi, Shenshen Lai, Wyeth W. Wasserman, Calvin K. Yip, Sarah Grasedieck, Hong Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
Xenotransplantation
medicine.medical_treatment Immunology Mice SCID Biology Biochemistry Transcriptome Mice chemistry.chemical_compound Drug Delivery Systems Mice Inbred NOD Cell Line Tumor Proto-Oncogene Proteins hemic and lymphatic diseases medicine Animals Humans Progenitor cell Sulfonamides Kinase Venetoclax Receptor Protein-Tyrosine Kinases Myeloid leukemia Cell Biology Hematology Bridged Bicyclo Compounds Heterocyclic Xenograft Model Antitumor Assays Axl Receptor Tyrosine Kinase Leukemia Myeloid Acute Cell killing chemistry Neoplastic Stem Cells Cancer research Stem cell |
| Zdroj: | Blood. 137:3641-3655 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | The abundance of genetic abnormalities and phenotypic heterogeneities in acute myeloid leukemia (AML) poses significant challenges to the development of improved treatments. Here, we demonstrated that a key growth arrest-specific gene 6/AXL axis is highly activated in cells from patients with AML, particularly in stem/progenitor cells. We developed a potent selective AXL inhibitor that has favorable pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation (PDX) models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in PDX models. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition, alone or in combination with venetoclax, potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells and shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. Inhibition of AXL or BCL-2 also differentially targets key signaling proteins to synergize in leukemic cell killing. These findings have a direct translational impact on the treatment of AML and other cancers with high AXL activity. |
| Databáze: | OpenAIRE |
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