ArticleBlood advances2019
Role of CYP3A4 in bone marrow microenvironment-mediated protection of FLT3/ITD AML from tyrosine kinase inhibitors.
Article in Blood advances, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 75 citations in OpenAlex.
- Pharmacological boosting of azacitidine/venetoclax in acute myeloid leukemia.Blood neoplasia · 2026Trial
- Quizartinib and omacetaxine mepesuccinate combination therapy in FLT3-ITD AML: a phase II trial.Nature communications · 2026Trial
- Mislocalisation of FLT3-ITD receptor contributes to MV4-11 leukaemia cell resistance to antibody-drug conjugate.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- A structure-based modeling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia.iScience · 2026Article
- Resistance to Targeted Therapy in AML: Current Challenges and Emerging Treatment Strategies.Journal of clinical medicine · 2026Review
- Relapse following FLT3 inhibitor cessation in FLT3-ITD-positive AML: lessons from two clinical cases.Annals of hematology · 2026Article
- Sterol Metabolism in Ovariectomized Rats: Potential Roles of Campesterol and 4β-Hydroxycholesterol in Osteoporosis.Lipids · 2026Article
- FLT3: A 35-Year Voyage from Discovery to the Next Generation of Targeted Therapy in AML.Cancers · 2025Review
- Counter-Therapeutic Strategies for Resistance of FLT3 Inhibitors in Acute Myeloid Leukemia.Cells · 2025Review
- Antipsychotic Chlorpromazine Suppresses STAT5 Signaling, Overcomes Resistance Mediated by the Gatekeeper Mutation FLT3-ITD/F691L, and Synergizes with Quizartinib in FLT3-ITD-Positive Cells.Current issues in molecular biology · 2025Article
- Review
- Review
- Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming.Journal of experimental & clinical cancer research : CR · 2025Article
- A New Histology-Based Prognostic Index for Acute Myeloid Leukemia: Preliminary Results for the "AML Urayasu Classification".Journal of clinical medicine · 2025Article
- Molecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer.Molecular biomedicine · 2025Review
- Overcoming the sorafenib resistance mechanism in FLT3-mutated acute myeloid leukemia: molecular basis and new targets.Frontiers in oncology · 2025Review
- FLT3 targeting in the modern era: from clonal selection to combination therapies.International journal of hematology · 2024Review
- Precision medicine in AML: overcoming resistance.International journal of hematology · 2024Review
- Review
- Shikonin Exerts an Antileukemia Effect against FLT3-ITD Mutated Acute Myeloid Leukemia Cells via Targeting FLT3 and Its Downstream Pathways.Acta haematologica · 2024Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
An intriguing aspect of the clinical activity of FMS-like tyrosine kinase 3 inhibitors (FLT3 TKIs) is their apparent higher activity against peripheral blasts from FLT3/internal tandem duplication (ITD) acute myeloid leukemia than marrow disease in the same patients. Accordingly, studies showed that the bone marrow microenvironment plays a role in FLT3 TKI resistance, although the underlying mechanisms are unclear. We recently identified a previously undescribed mechanism by which the bone marrow microenvironment can contribute to drug resistance: expression of cytochrome P450 enzymes (CYPs). In fact, bone marrow stromal cells (BMSCs) expressed most CYPs, including CYP3A4. Because hepatic CYP3A4 plays a role in the inactivation of several FLT3 TKIs, we explored the potential role of CYP3A4 in bone marrow microenvironment-mediated FLT3 TKI resistance. We found that CYP3A4 plays a major role in BMSC-mediated inhibition in the activity of 3 different FLT3 TKIs (sorafenib, quizartinib, and gilteritinib) against FLT3/ITD acute myeloid leukemia (AML). Furthermore, clarithromycin, a clinically active CYP3A4 inhibitor, significantly reversed the protective effects of BMSCs. We show, for the first time, that bone marrow stromal CYP3A4 contributes to FLT3 TKI resistance in the bone marrow. These results suggest that combining FLT3 TKIs with CYP3A4 inhibitors could be a promising strategy toward improving the activity of FLT3 TKIs.
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