ArticleJournal of molecular medicine (Berlin, Germany)2012
Therapeutic potential of MEK inhibition in acute myelogenous leukemia: rationale for "vertical" and "lateral" combination strategies.
Article in Journal of molecular medicine (Berlin, Germany), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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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
24 citing papers in PubMed, 41 citations in OpenAlex.
- Trial
- Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2014Trial
- Vitamin D Deficiency in Leukemia: Implications for Pathophysiology, Treatment, and Supportive Care.Nutrients · 2026Review
- Identification and validation of a novel prognostic model based on anoikis‑related genes in acute myeloid leukemia.Oncology letters · 2025Article
- MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases.International journal of oncology · 2023Article
- Article
- Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models.Haematologica · 2020Article
- Acute myeloid leukemia-induced T-cell suppression can be reversed by inhibition of the MAPK pathway.Blood advances · 2019Article
- Article
- Article
- Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models.Journal of experimental & clinical cancer research : CR · 2018Article
- Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells.Oncotarget · 2017Article
- Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia.Oncotarget · 2017Article
- PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.Scientific reports · 2017Article
- The pan-class I phosphatidyl-inositol-3 kinase inhibitor NVP-BKM120 demonstrates anti-leukemic activity in acute myeloid leukemia.Scientific reports · 2015Article
- Triple Akt inhibition as a new therapeutic strategy in T-cell acute lymphoblastic leukemia.Oncotarget · 2015Article
- Targeted Therapy of FLT3 in Treatment of AML-Current Status and Future Directions.Journal of clinical medicine · 2014Review
- Inhibiting CCN1 blocks AML cell growth by disrupting the MEK/ERK pathway.Cancer cell international · 2014Article
- Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor.PloS one · 2014Article
- The AKT inhibitor MK-2206 is cytotoxic in hepatocarcinoma cells displaying hyperphosphorylated AKT-1 and synergizes with conventional chemotherapy.Oncotarget · 2013Article
Corrections and comments
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Authors and funding
20 authors at 7 institutions in 3 countries.
Funding
Abstract
In hematological malignancies, constitutive activation of the RAF/MEK/ERK pathway is frequently observed, conveys a poor prognosis, and constitutes a promising target for therapeutic intervention. Here, we investigated the molecular and functional effects of pharmacological MEK inhibition in cell line models of acute myeloid leukemia (AML) and freshly isolated primary AML samples. The small-molecule, ATP-non-competitive, MEK inhibitor PD0325901 markedly inhibited ERK phosphorylation and growth of several AML cell lines and approximately 70 % of primary AML samples. Growth inhibition was due to G(1)-phase arrest and induction of apoptosis. Transformation by constitutively active upstream pathway elements (HRAS, RAF-1, and MEK) rendered FDC-P1 cells exquisitely prone to PD0325901-induced apoptosis. Gene and protein expression profiling revealed a selective effect of PD0325901 on ERK phosphorylation and compensatory upregulation of the RAF/MEK and AKT/p70( S6K ) kinase modules, potentially mediating resistance to drug-induced growth inhibition. Consequently, in appropriate cellular contexts, both "vertical" (i.e., inhibition of RAF and MEK along the MAPK pathway) and "lateral" (i.e., simultaneous inhibition of the MEK/ERK and mTOR pathways) combination strategies may result in synergistic anti-leukemic effects. Overall, MEK inhibition exerts potent growth inhibitory and proapoptotic activity in preclinical models of AML, particularly in combination with other pathway inhibitors. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective targeted strategies for the treatment of 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.