Trial reportBlood2007
MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825.
Trial report in Blood, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 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
25 citing papers in PubMed, 55 citations in OpenAlex.
- The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status.Haematologica · 2012Trial
- Src inhibition potentiates MCL-1 antagonist activity in acute myeloid leukemia.Signal transduction and targeted therapy · 2025Article
- Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK-ERK and NF-κB pathways in a model of chronic myeloid leukemia.Molecular oncology · 2018Article
- Inhibition of Ras-mediated signaling pathways in CML stem cells.Cellular oncology (Dordrecht, Netherlands) · 2015Review
- Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL⁺ leukemia cells.Leukemia research · 2015Article
- Glucosylceramide synthase promotes Bcl-2 expression via the ERK signaling pathway in the K562/A02 leukemia drug-resistant cell line.International journal of hematology · 2014Article
- Gambogic acid induces apoptosis in imatinib-resistant chronic myeloid leukemia cells via inducing proteasome inhibition and caspase-dependent Bcr-Abl downregulation.Clinical cancer research : an official journal of the American Association for Cancer Research · 2014Article
- Combined effects of PI3K and SRC kinase inhibitors with imatinib on intracellular calcium levels, autophagy, and apoptosis in CML-PBL cells.Cell cycle (Georgetown, Tex.) · 2013Article
- Src tyrosine kinase inhibits apoptosis through the Erk1/2- dependent degradation of the death accelerator Bik.Cell death and differentiation · 2012Article
- Tyrosine kinase gene fusions in cancer: translating mechanisms into targeted therapies.Journal of cellular and molecular medicine · 2012Review
- Article
- The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells.Leukemia · 2011Article
- HDAC inhibitors potentiate the activity of the BCR/ABL kinase inhibitor KW-2449 in imatinib-sensitive or -resistant BCR/ABL+ leukemia cells in vitro and in vivo.Clinical cancer research : an official journal of the American Association for Cancer Research · 2011Article
- Dasatinib impairs long-term expansion of leukemic progenitors in a subset of acute myeloid leukemia cases.Annals of hematology · 2010Article
- The bone marrow microenvironment as a sanctuary for minimal residual disease in CML.Biochemical pharmacology · 2010Review
- Inhibition of MEK/ERK1/2 sensitizes lymphoma cells to sorafenib-induced apoptosis.Leukemia research · 2010Article
- Article
- Contribution of BCR-ABL-independent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells.Cancer science · 2010Article
- Activation of the p38 Map kinase pathway is essential for the antileukemic effects of dasatinib.Leukemia & lymphoma · 2009Article
- Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Interactions between MEK1/2 inhibitors and the dual Abl/Src kinase inhibitor dasatinib (BMS-354825) were examined in chronic myeloid leukemia (CML) cell lines and primary specimens. Cotreatment of K562 or LAMA cells with subtoxic or marginally toxic concentrations of PD184352 (or U0126) and dasatinib synergistically potentiated mitochondrial damage, caspase activation, and apoptosis. Similar interactions were observed in CD34(+) cells from one CML patient-derived but not in a normal human CD34(+) bone marrow cell specimen. These interactions were associated with multiple perturbations in survival signaling pathways, including inactivation of Bcr/Abl, STAT5, and ERK1/2; down-regulation of Bcl-x(L) and Mcl-1; and dephosphorylation/activation of Bim. They were also associated with BAX/BAK conformational change, mitochondrial dysfunction, and caspase activation. Bim knockdown by shRNA suppressed BAX and BAK conformational change and protected cells from dasatinib/PD184352 lethality. Conversely, K562 cells ectopically expressing Mcl-1 or Bcl-x(L) were significantly less susceptible to dasatinib/PD184352 toxicity. Notably, the dasatinib/PD184352 regimen was active against leukemic cells exhibiting various forms of imatinib mesylate resistance, including Bcr/Abl overexpression, Lyn activation, and several Bcr/Abl kinase domain mutations (eg, E255K, M351T), but not T315I. Together, these findings suggest that strategies combining dasatanib with MEK1/2 inhibitors warrant further investigation in Bcr/Abl(+) malignancies, particularly in the setting of imatinib mesylate-resistant disease.
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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.