ArticleJournal of experimental & clinical cancer research : CR2019
Hyper-activation of Aurora kinase a-polo-like kinase 1-FOXM1 axis promotes chronic myeloid leukemia resistance to tyrosine kinase inhibitors.
Article in Journal of experimental & clinical cancer research : CR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It carries an expression of concern. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 18 citations in OpenAlex.
- Editorial expression of concern: Hyper-activation of Aurora kinase a-pololike kinase 1-FOXM1 axis promotes chronic myeloid leukemia resistance to tyrosine kinase inhibitors.Journal of experimental & clinical cancer research : CR · 2026Article
- Article
- SETD2 loss of function is a recurrent event in advanced-phase chronic myeloid leukemia and contributes to genomic instability: SETD2 loss in Chronic Myeloid Leukemia.Clinical and translational medicine · 2025Article
- The Functional Transcriptomic Landscape Informs Therapeutic Strategies in Multiple Myeloma.Cancer research · 2025Article
- Combination of an aurora kinase inhibitor and the ABL tyrosine kinase inhibitor asciminib against ABL inhibitor-resistant CML cells.Medical oncology (Northwood, London, England) · 2024Article
- Phosphorylation-Dependent Regulation of WNT/Beta-Catenin Signaling.Frontiers in oncology · 2022Review
- Overcoming Resistance to Kinase Inhibitors: The Paradigm of Chronic Myeloid Leukemia.OncoTargets and therapy · 2022Review
- Polo-like kinase-1, Aurora kinase A and WEE1 kinase are promising druggable targets in CML cells displaying BCR::ABL1-independent resistance to tyrosine kinase inhibitors.Frontiers in oncology · 2022Article
- A narrative review of research progress on FoxM1 in breast cancer carcinogenesis and therapeutics.Annals of translational medicine · 2021Review
- Current Views on the Interplay between Tyrosine Kinases and Phosphatases in Chronic Myeloid Leukemia.Cancers · 2021Review
- Identification of Aurora Kinase A as a Biomarker for Prognosis in Obesity Patients with Early Breast Cancer.OncoTargets and therapy · 2020Article
Corrections and comments
- Expression of concern
Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundChronic myeloid leukemia (CML) is a myeloproliferative disease caused by the constitutive tyrosine kinase (TK) activity of the BCR-ABL1 fusion protein. Accordingly, TK inhibitors have drastically changed the disease prognosis. However, persistence of the transformed hematopoiesis even in patients who achieved a complete response to TK inhibitors and the disease relapse upon therapy discontinuation represent a major obstacle to CML cure.
methodsThiostrepton, Danusertib and Volasertib were used to investigate the effects of FOXM1, AKA and Plk1 inhibition in K562-S and K562-R cells. Apoptotic cell death was quantified by annexin V/propidium iodide staining and flow cytometry. Quantitative reverse transcription (RT)-PCR was used to assess BCR-ABL1, FOXM1, PLK1 and AURKA expression. Protein expression and activation was assessed by Western Blotting (WB). Clonogenic assay were performed to confirm K562-R resistance to Imatinib and to evaluate cells sensitivity to the different drugs.
resultsHere we proved that BCR-ABL1 TK-dependent hyper-activation of Aurora kinase A (AURKA)-Polo-like kinase 1 (PLK1)-FOXM1 axis is associated with the outcome of Imatinib (IM) resistance in an experimental model (K562 cell line) and bone marrow hematopoietic cells. Notably, such a biomolecular trait was detected in the putative leukemic stem cell (LSC) compartment characterized by a CD34+ phenotype. Constitutive phosphorylation of FOXM1 associated with BCR-ABL1 TK lets FOXM1 binding with β-catenin enables β-catenin nuclear import and recruitment to T cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription complex, hence supporting leukemic cell proliferation and survival. Lastly, the inhibition of single components of AURKA-PLK1-FOXM1 axis in response to specific drugs raises the expression of growth factor/DNA damage-inducible gene a (GADD45a), a strong inhibitor of AURKA and, as so, a critical component whose induction may mediate the eradication of leukemic clone.
conclusionsOur conclusion is that AURKA, PLK1 and FOXM1 inhibition may be considered as a promising therapeutic approach to cure CML.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.