ArticleClinical cancer research : an official journal of the American Association for Cancer Research2014
Reversal of acquired drug resistance in FLT3-mutated acute myeloid leukemia cells via distinct drug combination strategies.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2014. 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, 53 citations in OpenAlex.
- ATO alleviates T-cell immunosuppression by inducing apoptosis-associated secretion of IL-2 in FLT3-ITD-mutated acute myeloid leukemia.Translational oncology · 2026Article
- Recent Advances in FLT3-Based Dual Inhibitors: A Promising Strategy for the Treatment of Acute Myeloid Leukemia.Current medicinal chemistry · 2026Review
- Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition with Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild-type Acute Myeloid Leukemias.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- FLT3-targeted therapy restores GATA1 pathway function in NPM1/FLT3-ITD mutated acute myeloid leukaemia.EJHaem · 2023Article
- Pathogenic mutation hotspots in protein kinase domain structure.Protein science : a publication of the Protein Society · 2023Article
- Concomitant targeting of FLT3 and BTK overcomes FLT3 inhibitor resistance in acute myeloid leukemia through the inhibition of autophagy.Haematologica · 2023Article
- Preclinical and Pilot Study of Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib, with Sorafenib in Acute Myeloid Leukemia and FLT3-Internal Tandem Duplication.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- A novel approach for relapsed/refractory FLT3Molecular cancer · 2022Article
- A review of FLT3 inhibitors in acute myeloid leukemia.Blood reviews · 2022Review
- Genomic Abnormalities as Biomarkers and Therapeutic Targets in Acute Myeloid Leukemia.Cancers · 2021Review
- Strategies targeting FLT3 beyond the kinase inhibitors.Pharmacology & therapeutics · 2021Review
- High-throughput proteomic profiling reveals mechanisms of action of AMG925, a dual FLT3-CDK4/6 kinase inhibitor targeting AML and AML stem/progenitor cells.Annals of hematology · 2021Article
- Multiple mutations within individual oncogenes.Cancer science · 2021Review
- Pan-RAF Inhibition Shows Anti-Leukemic Activity inCancers · 2020Article
- The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML.Nature reviews. Cancer · 2020Review
- Overcoming adaptive therapy resistance in AML by targeting immune response pathways.Science translational medicine · 2019Article
- Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis inHaematologica · 2018Article
- Disruption of Wnt/β-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition inClinical cancer research : an official journal of the American Association for Cancer Research · 2018Article
- Review
- TumorOncotarget · 2017Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
purposeFMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (FLT3-ITD) mutations are common in patients with acute myeloid leukemia (AML). These patients regularly develop resistance to FLT3 inhibitors suggesting that targeted combination drug strategies are needed to enhance AML therapy efficacy. EXPERIMENTAL
designAcquired point mutations of FLT3-ITD gene were screened using cDNA-based sequencing approach in vitro sorafenib-resistant cells, which were developed by long-term exposure of Ba/F3-ITD to increasing doses of sorafenib, and in FLT3-ITD mutated AML patients, who developed relapse following sorafenib therapy. Drug effects (e.g., proliferation inhibition, apoptosis induction, and changes in signal transduction protein expression) were assessed in AML cells harboring the point mutations in vitro and in FLT3-ITD-mutated AML patient samples.
resultsWe identified several acquired point mutations in the tyrosine kinase domains (TKD) of the FLT3 gene in sorafenib-resistant murine leukemia cell line carrying human FLT3-ITD mutations, which were also detected in two of four sorafenib-resistant patient samples. Engineering these point mutations into Ba/F3-ITD cells generated sublines that demonstrated varying degrees of sorafenib [a type II tyrosine kinase inhibitor (TKI)] resistance. A similar pattern of resistance could be observed by exposing these sublines to the other type II TKIs AC220 and MLN518. However, these sublines retained sensitivity to the type I TKIs PKC412 or crenolanib. The combination of crenolanib with sorafenib demonstrated marked cytotoxic effects in all of the sorafenib-resistant sublines.
conclusionsThese combination strategies could be clinically important in reversing acquired resistance to FLT3 inhibition in AML.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.