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FLT3: A 35-Year Voyage from Discovery to the Next Generation of Targeted Therapy in AML.
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Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
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Department of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022338 Bucharest, Romania
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The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Authors to whom correspondence should be addressed.
Cancers 2025, 17(21), 3415; https://doi.org/10.3390/cancers17213415 (registering DOI)
Submission received: 25 September 2025
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Revised: 20 October 2025
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Accepted: 22 October 2025
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Published: 23 October 2025
(This article belongs to the Special Issue From Bench to Bedside: Novel Molecular Targets and Therapeutic Strategies in AML)
Simple Summary
Protein kinases are fundamental regulators of cellular function, orchestrating proliferation, survival, and differentiation through reversible phosphorylation. Their importance extends beyond normal physiology: dysregulated kinase activity is a defining feature of cancer, where constitutive signaling sustains malignant growth and therapy resistance. Among them, receptor tyrosine kinases occupy a central role by transmitting extracellular cues into potent intracellular programs. One such receptor, FMS-like tyrosine kinase 3 (FLT3), is expressed at high levels in hematopoietic stem and progenitor cells, where it maintains homeostasis and supports immune development, particularly dendritic cell biology. In acute myeloid leukemia (AML), FLT3 mutations—most often internal tandem duplications (ITDs) or tyrosine kinase domain substitutions (TKDs)—constitute some of the most frequent genetic alterations and are strongly associated with poor prognosis. The therapeutic targeting of FLT3 represents a paradigm for translating kinase biology into clinical progress. Decades of preclinical and clinical work culminated in the approval of three potent FLT3 inhibitors—midostaurin, gilteritinib, and quizartinib—that, together with stem cell transplantation, have dramatically improved outcomes for patients with FLT3-mutant AML. Yet, as with many kinase inhibitors, resistance remains a barrier, fueling efforts toward rational combination therapies and measurable residual disease-directed strategies. The FLT3 story illustrates both the promise and the ongoing challenges of kinase inhibition in modern cancer care.
Abstract
FMS-like tyrosine kinase 3 (FLT3) is a crucial regulator of normal hematopoiesis, with high expression in hematopoietic stem and progenitor cells. Beyond its role in stem cell survival and proliferation, FLT3 signaling is essential for immune regulation, particularly dendritic cell differentiation and NK cell expansion. In acute myeloid leukemia (AML), FLT3 mutations—most commonly internal tandem duplications (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD) substitutions—are among the most frequent genetic alterations, driving constitutive activation of proliferative and antiapoptotic pathways and conferring adverse prognosis. The clinical development of FLT3 inhibitors has been a decades-long endeavor. Early multikinase agents established proof-of-concept but were hampered by off-target effects and incomplete efficacy. The subsequent generation of potent and selective inhibitors has transformed outcomes, culminating in FDA approvals of midostaurin, quizartinib, and gilteritinib. Together with allogeneic transplantation, these agents have reshaped the treatment paradigm for FLT3-mutant AML, converting a historically high-risk subset into one with realistic prospects for long-term survival. Despite these advances, challenges remain. Resistance emerges through cell-intrinsic mechanisms such as acquisition of secondary TKD or RAS pathway mutations, metabolic reprogramming, and antiapoptotic shifts, as well as cell-extrinsic mechanisms mediated by the bone marrow microenvironment, including cytokine support, stromal CYP3A4 metabolism, and retinoid inactivation. These pathways sustain measurable residual disease (MRD), the key predictor of relapse. Rational combination strategies and MRD-directed approaches are therefore essential to fully realize the curative potential of FLT3 inhibition.
