ArticleScientific reports2019
MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
20 citing papers in PubMed, 32 citations in OpenAlex.
- Resistance to Targeted Therapy in AML: Current Challenges and Emerging Treatment Strategies.Journal of clinical medicine · 2026Review
- Deciphering Multitarget Mechanisms of Cardiac Glycosides in Acute Myeloid Leukemia Using a Network Pharmacology and Molecular Docking.Drug design, development and therapy · 2026Article
- Targeting NPC1 in Renal Cell Carcinoma.Cancers · 2024Article
- Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia.Leukemia · 2023Article
- Molecular Profile of Canine Hemangiosarcoma and Potential Novel Therapeutic Targets.Veterinary sciences · 2023Review
- Early response evaluation by single cell signaling profiling in acute myeloid leukemia.Nature communications · 2023Article
- Augmenting Venetoclax Activity Through Signal Transduction in AML.Journal of cellular signaling · 2023Article
- CYLD stimulates macrophage phagocytosis of leukemic cells through STAT1 signalling in acute myeloid leukemia.PloS one · 2023Article
- Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective.Signal transduction and targeted therapy · 2022Review
- Review
- Resistance to targeted therapies: delving into FLT3 and IDH.Blood cancer journal · 2022Review
- RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia.Leukemia · 2022Article
- New Perspectives in Treating Acute Myeloid Leukemia: Driving towards a Patient-Tailored Strategy.International journal of molecular sciences · 2022Review
- Refining AML Treatment: The Role of Genetics in Response and Resistance Evaluation to New Agents.Cancers · 2022Review
- Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma.Nature communications · 2022Article
- Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches.OncoTargets and therapy · 2022Review
- Genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways mediating sorafenib resistance in acute myeloid leukemia.Haematologica · 2022Article
- Phosphoproteomic Characterization of Primary AML Samples and Relevance for Response Toward FLT3-inhibitors.HemaSphere · 2021Article
- Targeted therapy of human leukemia xenografts in immunodeficient zebrafish.Scientific reports · 2021Article
- Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
FMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML). Several tyrosine kinase inhibitors (TKIs) targeting FLT3 have been evaluated clinically, but their effects are limited when used in monotherapy due to the emergence of drug-resistance. Thus, a better understanding of drug-resistance pathways could be a good strategy to explore and evaluate new combinational therapies for AML. Here, we used phosphoproteomics to identify differentially-phosphorylated proteins in patients with AML and TKI resistance. We then studied resistance mechanisms in vitro and evaluated the efficacy and safety of rational combinational therapy in vitro, ex vivo and in vivo in mice. Proteomic and immunohistochemical studies showed the sustained activation of ERK1/2 in bone marrow samples of patients with AML after developing resistance to FLT3 inhibitors, which was identified as a common resistance pathway. We examined the concomitant inhibition of MEK-ERK1/2 and FLT3 as a strategy to overcome drug-resistance, finding that the MEK inhibitor trametinib remained potent in TKI-resistant cells and exerted strong synergy when combined with the TKI midostaurin in cells with mutated and wild-type FLT3. Importantly, this combination was not toxic to CD34+ cells from healthy donors, but produced survival improvements in vivo when compared with single therapy groups. Thus, our data point to trametinib plus midostaurin as a potentially beneficial therapy in patients with AML.
Indexed as
Identifiers
What OpenQuestion holds
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.