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Anlotinib synergizes with venetoclax to induce mitotic catastrophe in acute myeloid leukemia.
- Source :
-
Cancer letters [Cancer Lett] 2024 Jul 01; Vol. 593, pp. 216970. Date of Electronic Publication: 2024 May 18. - Publication Year :
- 2024
-
Abstract
- Venetoclax is a BCL2-targeted drug employed in treating various cancers, particularly hematologic malignancies. Venetoclax combination therapies are increasingly recognized as promising treatment strategies for acute myeloid leukemia (AML). In this study, we conducted an unbiased drug screen and identified anlotinib, a promising multi-targeted receptor tyrosine kinase inhibitor with oral activity currently utilized in the treatment of solid tumor, as a potent enhancer of venetoclax's anticancer activity in AML. Our investigation encompassed AML cell lines, primary cells, and mouse models, demonstrating effective low-dose combination therapy of anlotinib and venetoclax with minimal cytopenia or organ damage. Proteomic analysis revealed abnormal mitotic signals induced by this combination in AML cells. Mechanistically, anlotinib synergized with venetoclax by suppressing ARPP19 protein, leading to sustained activation of PP2A-B55δ. This inhibited AML cells from entering the mitotic phase, culminating in mitotic catastrophe and apoptosis. Additionally, we identified a specific synthetic lethal vulnerability in AML involving an ARPP19 mutation at S62 phosphorylation. These findings underscore the therapeutic potential of anlotinib and venetoclax combination therapy in AML, warranting further clinical investigation.<br />Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest.<br /> (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Humans
Animals
Mice
Cell Line, Tumor
Antineoplastic Combined Chemotherapy Protocols pharmacology
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Leukemia, Myeloid, Acute drug therapy
Leukemia, Myeloid, Acute pathology
Leukemia, Myeloid, Acute genetics
Leukemia, Myeloid, Acute metabolism
Sulfonamides pharmacology
Sulfonamides administration & dosage
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Quinolines pharmacology
Quinolines administration & dosage
Mitosis drug effects
Indoles pharmacology
Indoles administration & dosage
Drug Synergism
Xenograft Model Antitumor Assays
Apoptosis drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 593
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 38763475
- Full Text :
- https://doi.org/10.1016/j.canlet.2024.216970