ArticlePloS one2011
Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 44 citations in OpenAlex.
- Novel targeted therapies in chronic myeloid leukemia.Pharmaceutical science advances · 2024Review
- Developing therapeutic approaches for chronic myeloid leukemia: a review.Molecular and cellular biochemistry · 2023Review
- Sorafenib Chemosensitization by Caryophyllane Sesquiterpenes in Liver, Biliary, and Pancreatic Cancer Cells: The Role of STAT3/ABC Transporter Axis.Pharmaceutics · 2022Article
- Infigratinib (BGJ 398), a Pan-FGFR Inhibitor, Targets P-Glycoprotein and Increases Chemotherapeutic-Induced Mortality of Multidrug-Resistant Tumor Cells.Biomedicines · 2022Article
- Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer.Molecules (Basel, Switzerland) · 2021Review
- Insulin-like growth factor-binding proteins play a significant role in the molecular response to imatinib in chronic myeloid leukemia patients.Experimental and therapeutic medicine · 2020Article
- Antimicrobial Peptide Reverses ABCB1-Mediated Chemotherapeutic Drug Resistance.Frontiers in pharmacology · 2020Article
- Recent advances in the development of Aurora kinases inhibitors in hematological malignancies.Therapeutic advances in hematology · 2015Review
- Article
- Association between acquired resistance to PLX4032 (vemurafenib) and ATP-binding cassette transporter expression.BMC research notes · 2014Article
- A 'telomere-associated secretory phenotype' cooperates with BCR-ABL to drive malignant proliferation of leukemic cells.Leukemia · 2014Article
- Tyrosine kinase inhibitors as reversal agents for ABC transporter mediated drug resistance.Molecules (Basel, Switzerland) · 2014Review
- ABC transporters in multi-drug resistance and ADME-Tox of small molecule tyrosine kinase inhibitors.Pharmaceutical research · 2014Review
- A novel mouse model for inhibition of DOHH-mediated hypusine modification reveals a crucial function in embryonic development, proliferation and oncogenic transformation.Disease models & mechanisms · 2014Article
- Identification of a cancer stem cell-like side population in the HeLa human cervical carcinoma cell line.Oncology letters · 2013Article
- Oral anticancer drugs: mechanisms of low bioavailability and strategies for improvement.Clinical pharmacokinetics · 2013Review
- Myeloprotection by cytidine deaminase gene transfer in antileukemic therapy.Neoplasia (New York, N.Y.) · 2013Review
- Evaluation of deoxyhypusine synthase inhibitors targeting BCR-ABL positive leukemias.Investigational new drugs · 2012Article
- Protein-protein-interaction network organization of the hypusine modification system.Molecular & cellular proteomics : MCP · 2012Article
- The novel BCR-ABL and FLT3 inhibitor ponatinib is a potent inhibitor of the MDR-associated ATP-binding cassette transporter ABCG2.Molecular cancer therapeutics · 2012Article
Corrections and comments
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Authors and funding
13 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The success of Imatinib (IM) therapy in chronic myeloid leukemia (CML) is compromised by the development of IM resistance and by a limited IM effect on hematopoietic stem cells. Danusertib (formerly PHA-739358) is a potent pan-aurora and ABL kinase inhibitor with activity against known BCR-ABL mutations, including T315I. Here, the individual contribution of both signaling pathways to the therapeutic effect of Danusertib as well as mechanisms underlying the development of resistance and, as a consequence, strategies to overcome resistance to Danusertib were investigated. Starting at low concentrations, a dose-dependent inhibition of BCR-ABL activity was observed, whereas inhibition of aurora kinase activity required higher concentrations, pointing to a therapeutic window between the two effects. Interestingly, the emergence of resistant clones during Danusertib exposure in vitro occurred considerably less frequently than with comparable concentrations of IM. In addition, Danusertib-resistant clones had no mutations in BCR-ABL or aurora kinase domains and remained IM-sensitive. Overexpression of Abcg2 efflux transporter was identified and functionally validated as the predominant mechanism of acquired Danusertib resistance in vitro. Finally, the combined treatment with IM and Danusertib significantly reduced the emergence of drug resistance in vitro, raising hope that this drug combination may also achieve more durable disease control in vivo.
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