ArticlePloS one2017
Cholesterol esterification inhibition and imatinib treatment synergistically inhibit growth of BCR-ABL mutation-independent resistant chronic myelogenous leukemia.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 64 citations in OpenAlex.
- Spectroscopic Signature of Apoptosis Induced by Venetoclax in Philadelphia-Positive Acute Lymphoblastic Leukemia.Analytical chemistry · 2026Article
- Hypercholesterolemia-induced impairment in sorafenib functionality is overcome by avasimibe co-treatment.Journal of biosciences · 2026Article
- Cholesterol in hematological malignancies: metabolism, mechanisms, and clinical implications.Frontiers in immunology · 2026Review
- Lipid Storage and Therapy Resistance in Chronic Myeloid Leukaemia: A Novel Perspective on Targeting Metabolic Vulnerabilities.Cancers · 2025Review
- Targeting ACAT1 in cancer: from threat to treatment.Frontiers in oncology · 2024Review
- Acyl-coenzyme A: cholesterol acyltransferase inhibitor avasimibe suppresses tumorigenesis and induces G1-phase cell-cycle arrest by activating PPARγ signaling pathway in bladder cancer.Journal of Cancer · 2024Article
- Inhibition of Integrin αCell adhesion & migration · 2023Article
- Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics.Journal of hematology & oncology · 2023Review
- Functional significance of cholesterol metabolism in cancer: from threat to treatment.Experimental & molecular medicine · 2023Review
- Comprehensive analysis of the clinical and biological significances of cholesterol metabolism in lower-grade gliomas.BMC cancer · 2023Article
- Reversible translocation of acyl-CoA:cholesterol acyltransferase (ACAT) between the endoplasmic reticulum and vesicular structures.Frontiers in molecular biosciences · 2023Article
- Cholesterol esterification and p53-mediated tumor suppression.Exploration of targeted anti-tumor therapy · 2023Article
- Association between Germline Single-Nucleotide Variants in ADME Genes and Major Molecular Response to Imatinib in Chronic Myeloid Leukemia Patients.Journal of clinical medicine · 2022Article
- ACAT-1-Regulated Cholesteryl Ester Accumulation Modulates Gemcitabine Resistance in Biliary Tract Cancer.Annals of surgical oncology · 2022Article
- Lipid Metabolism in Biliary Tract Cancer: A New Therapeutic Target?Annals of surgical oncology · 2022Article
- Article
- Review
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- Mass Cytometry in Hematologic Malignancies: Research Highlights and Potential Clinical Applications.Frontiers in oncology · 2021Review
- Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities.Nature metabolism · 2020Review
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Since the advent of tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, and dasatinib, chronic myelogenous leukemia (CML) prognosis has improved greatly. However, ~30-40% of patients develop resistance to imatinib therapy. Although most resistance is caused by mutations in the BCR-ABL kinase domain, 50-85% of these patients develop resistance in the absence of new mutations. In these cases, targeting other pathways may be needed to regain clinical response. Using label-free Raman spectromicroscopy, we evaluated a number of leukemia cell lines and discovered an aberrant accumulation of cholesteryl ester (CE) in CML, which was found to be a result of BCR-ABL kinase activity. CE accumulation in CML was found to be a cancer-specific phenomenon as untransformed cells did not accumulate CE. Blocking cholesterol esterification with avasimibe, a potent inhibitor of acyl-CoA cholesterol acyltransferase 1 (ACAT-1), significantly suppressed CML cell proliferation in Ba/F3 cells with the BCR-ABLT315I mutation and in K562 cells rendered imatinib resistant without mutations in the BCR-ABL kinase domain (K562R cells). Furthermore, the combination of avasimibe and imatinib caused a profound synergistic inhibition of cell proliferation in K562R cells, but not in Ba/F3T315I. This synergistic effect was confirmed in a K562R xenograft mouse model. Analysis of primary cells from a BCR-ABL mutation-independent imatinib resistant patient by mass cytometry suggested that the synergy may be due to downregulation of the MAPK pathway by avasimibe, which sensitized the CML cells to imatinib treatment. Collectively, these data demonstrate a novel strategy for overcoming BCR-ABL mutation-independent TKI resistance in CML.
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