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Updated: Jul 14, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem
C Brendel1, C Scharenberg, M Dohse
1Department of Hematology, Oncology and Immunology, Philipps-University Marburg, Baldingerstrasse, Marburg, Germany. brendelc@mailer.uni-marburg.de
Abstract:
The majority of chronic phase chronic myeloid leukemia (CML) patients treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate maintain durable responses to the drug. However, most patients relapse after withdrawal of imatinib and advanced stage patients often develop drug resistance. As CML is considered a hematopoietic stem cell cancer, it has been postulated that inherent protective mechanisms lead to relapse in patients. The ATP binding-cassette transporters ABCB1 (MDR-1; P-glycoprotein) and ABCG2 are highly expressed on primitive hematopoietic stem cells (HSCs) and have been shown to interact with TKIs. Herein we demonstrate a dose-dependent, reversible inhibition of ABCG2-mediated Hoechst 33342 dye efflux in primary human and murine HSC by both imatinib and nilotinib (AMN107), a novel aminopyrimidine inhibitor of BCR-ABL. ABCG2-transduced K562 cells were protected from imatinib and nilotinib-mediated cell death and from downregulation of P-CRKL. Moreover, photoaffinity labeling revealed interaction of both TKIs with ABCG2 at the substrate binding sites as they compete with the binding of [(125)I] IAAP and also stimulate the transporter's ATPase activity. Therefore, our evidence suggests for the role of ABC transporters in resistance to TKI on primitive HSCs and CML stem cells and provides a rationale how TKI resistance can be overcome in vivo.
Insights
Chronic myeloid leukemia (CML) stem cells may resist tyrosine kinase inhibitors (TKIs) like imatinib via ABCG2 transporters. This interaction offers a strategy to overcome TKI resistance in CML patients.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- Chronic myeloid leukemia (CML) often involves relapse and drug resistance despite initial TKI treatment.
- CML is a stem cell cancer, suggesting inherent protective mechanisms contribute to relapse.
- ATP binding-cassette transporters ABCB1 and ABCG2 are present on hematopoietic stem cells (HSCs) and interact with TKIs.
Purpose of the Study:
- To investigate the role of ABCG2 transporters in TKI resistance in CML stem cells.
- To determine if imatinib and nilotinib interact with ABCG2 and affect its function.
- To provide a rationale for overcoming TKI resistance in vivo.
Main Methods:
- Assessed inhibition of ABCG2-mediated dye efflux in HSCs by imatinib and nilotinib.
- Utilized ABCG2-transduced K562 cells to evaluate protection from TKI-mediated cell death and P-CRKL downregulation.
- Employed photoaffinity labeling to study TKI interaction with ABCG2 binding sites and ATPase activity.
Main Results:
- Imatinib and nilotinib inhibited ABCG2-mediated dye efflux in a dose-dependent manner.
- ABCG2 conferred protection to cells against imatinib and nilotinib, including preventing P-CRKL downregulation.
- TKIs interacted with ABCG2 at substrate binding sites, competing with [(125)I] IAAP and stimulating ATPase activity.
Conclusions:
- ABCG2 transporters play a role in TKI resistance in primitive HSCs and CML stem cells.
- The interaction between TKIs and ABCG2 provides a potential mechanism for overcoming drug resistance.
- Findings suggest strategies to overcome TKI resistance in CML patients.
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