ArticlePloS one2013
Selective Akt inhibitors synergize with tyrosine kinase inhibitors and effectively override stroma-associated cytoprotection of mutant FLT3-positive AML cells.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
27 citing papers in PubMed.
- Review
- Article
- Developments and challenges of FLT3 inhibitors in acute myeloid leukemia.Frontiers in oncology · 2022Review
- PP2A-activating Drugs Enhance FLT3 Inhibitor Efficacy through AKT Inhibition-Dependent GSK-3β-Mediated c-Myc and Pim-1 Proteasomal Degradation.Molecular cancer therapeutics · 2021Article
- Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms.Leukemia · 2020Article
- Profile of Quizartinib for the Treatment of Adult Patients with Relapsed/Refractory FLT3-ITD-Positive Acute Myeloid Leukemia: Evidence to Date.Cancer management and research · 2020Review
- LAM-003, a new drug for treatment of tyrosine kinase inhibitor-resistant FLT3-ITD-positive AML.Blood advances · 2019Article
- Overcoming adaptive therapy resistance in AML by targeting immune response pathways.Science translational medicine · 2019Article
- Emerging treatment paradigms with FLT3 inhibitors in acute myeloid leukemia.Therapeutic advances in hematology · 2019Review
- Therapeutic Vulnerabilities inInternational journal of molecular sciences · 2018Article
- Article
- A Facile, In Vitro 384-Well Plate System to Model Disseminated Tumor Cells in the Bone Marrow Microenvironment.Methods in molecular biology (Clifton, N.J.) · 2018Article
- Midostaurin: a novel therapeutic agent for patients with FLT3-mutated acute myeloid leukemia and systemic mastocytosis.Therapeutic advances in hematology · 2017Review
- FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions.Molecular cancer therapeutics · 2017Review
- Identification of Existing Drugs That Effectively Target NTRK1 and ROS1 Rearrangements in Lung Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Article
- The Role of the Central Nervous System Microenvironment in Pediatric Acute Lymphoblastic Leukemia.Frontiers in pediatrics · 2017Review
- Systematic Quality Control Analysis of LINCS Data.CPT: pharmacometrics & systems pharmacology · 2016Article
- NVP-TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P-glycoprotein (PGP1) function.British journal of pharmacology · 2016Article
- Modeling selective elimination of quiescent cancer cells from bone marrow.Neoplasia (New York, N.Y.) · 2015Article
- Targeting PI3K/AKT/mTOR network for treatment of leukemia.Cellular and molecular life sciences : CMLS · 2015Review
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
objectivesTyrosine kinase inhibitor (TKI)-treated acute myeloid leukemia (AML) patients commonly show rapid and significant peripheral blood blast cell reduction, however a marginal decrease in bone marrow blasts. This suggests a protective environment and highlights the demand for a better understanding of stromal:leukemia cell communication. As a strategy to improve clinical efficacy, we searched for novel agents capable of potentiating the stroma-diminished effects of TKI treatment of mutant FLT3-expressing cells.
methodsWe designed a combinatorial high throughput drug screen using well-characterized kinase inhibitor-focused libraries to identify novel kinase inhibitors capable of overriding stromal-mediated resistance to TKIs, such as PKC412 and AC220. Standard liquid culture proliferation assays, cell cycle and apoptosis analysis, and immunoblotting were carried out with cell lines or primary AML to validate putative candidates from the screen and characterize the mechanism(s) underlying observed synergy. RESULTS AND
conclusionsOur study led to the observation of synergy between selective Akt inhibitors and FLT3 inhibitors against mutant FLT3-positive AML in either the absence or presence of stroma. Our findings are consistent with evidence that Akt activation is characteristic of mutant FLT3-transformed cells, as well as observed residual Akt activity following FLT3 inhibitor treatment. In conclusion, our study highlights the potential importance of Akt as a signaling factor in leukemia survival, and supports the use of the co-culture chemical screen to identify agents able to potentiate TKI anti-leukemia activity in a cytoprotective microenvironment.
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Registered trials
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