Mechanism of action of the multikinase inhibitor Foretinib

Dufies, Maeva; Jacquel, Arnaud; Robert, Guillaume; Cluzeau, Thomas; Puissant, Alexandre; Fenouille, Nina; Legros, Laurence; Raynaud, Sophie; Cassuto, Jill‐Patrice; Luciano, Fréderic; Auberger, Patrick

doi:10.4161/cc.10.23.18323

Cited by 28 publications

(26 citation statements)

References 22 publications

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“…The reasons underlying tetraploidy in SKM1-R cell is currently unknown. We have shown previously that foretinib, a Polo Like Kinase 1 (PLK1) inhibitor induced polyploidy in an imatinib-resistant K562 cell line via a caspase-2-dependent mechanism [20]. However, PLK1 was found to be expressed at identical levels in SKM1-S and SKM1-R cell lines (results not shown).…”

Section: Resultsmentioning

confidence: 93%

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Phenotypic and genotypic characterization of azacitidine-sensitive and resistant SKM1 myeloid cell lines

et al. 2014

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In the present study, we provide a comparative phenotypic and genotypic analysis of azacitidine-sensitive and resistant SKM-1 cell lines. Morphologically, SKM1-R exhibited increase in cell size that accounts for by enhanced ploidy in a majority of cells as shown by cell cycle and karyotype analysis. No specific Single Nucleotide Polymorphism (SNP) alteration was found in SKM1-R cells compared to their SKM1-S counterpart. Comparative pangenomic profiling revealed the up-regulation of a panel of genes involved in cellular movement, cell death and survival and down-regulation of genes required for cell to cell signaling and free radical scavenging in SKM1-R cells. We also searched for mutations frequently associated with myelodysplastic syndromes (MDS) and found that both cell lines harbored mutations in TET2, ASLX1 and TP53. Collectively, our data show that despite their different morphological and phenotypic features, SKM1-S and SKM1-R cells exhibited similar genotypic characteristics. Finally, pangenomic profiling identifies new potential pathways to be targeted to circumvent AZA-resistance. In conclusion, SKM1-R cells represent a valuable tool for the validation of new therapeutic intervention in MDS.

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Section: Resultsmentioning

confidence: 93%

“…Cells were next incubated in PBS, 3 μg/ml RNase A and 40 μg/ml of propidium iodide (PI) for 30 min at 4°C. Cell distribution across the different phases of the cell cycle or DNA content was analyzed with a Miltenyi cytometer [20]. …”

Section: Methodsmentioning

confidence: 99%

Phenotypic and genotypic characterization of azacitidine-sensitive and resistant SKM1 myeloid cell lines

et al. 2014

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“…45 For cell cycle analysis, a standard PI/RNase A staining was performed. 46 Samples were analyzed on an FC500 flow cytometer (Beckman Coulter) with the appropriate software (CXP, Beckman Coulter).…”

Section: Acknowledgementsmentioning

confidence: 99%

Activity of the selective IκB kinase inhibitor BMS-345541 against T-cell acute lymphoblastic leukemia

et al. 2012

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“…Foretinib not only targets angiogenesis but, proliferation of the tumor. The substance has been found to inhibit the phosphorylation of MET, which is hepatocyte growth factor (HGF)-induced, and VEGF-induced kinase phosphorylation, thereby inhibiting both, HGF and VEGF dependent responses [142][143][144].…”

Section: Foretinibmentioning

confidence: 99%

Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

2015

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Scientists have identified the impact of angiogenesis on tumor growth and survival. Among other efficient drugs, several small-molecule tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor (VEGFR) have been developed and have already been integrated into the treatment of various advanced malignancies. This review provides a compilation of current knowledge on the pharmacokinetic aspects of all VEGFR-TKIs already approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and of those still under investigation. Additional information on substance metabolism, potential for drug-drug interactions (DDIs), and the need for dose adaptation in patients with predominant renal and/or hepatic impairment has been included. All TKIs introduced in this review were administered orally, allowing for easy drug handling for healthcare professionals and patients. For almost all substances, the maximum plasma concentrations were reached within a short period of time. The majority of the substances showed a high plasma protein binding and their excretion occurred via the feces and, to a lesser extent, via the urine. In most cases, dose adaptation in patients with mild to moderate renal or hepatic impairment is not recommended. Cytochrome P450 (CYP) 3A4 was found to play a crucial role in the drug metabolic processes of many compounds. In order to prevent unwanted DDIs, co-administration of VEGFR TKIs together with CYP3A4 inhibitors or inducers should be avoided. Throughout all TKIs, the data indicate high inter-individual variability. The causes of this are still unclear and require further research to allow for individualization of treatment regimens.

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Mechanism of action of the multikinase inhibitor Foretinib

Cited by 28 publications

References 22 publications

Phenotypic and genotypic characterization of azacitidine-sensitive and resistant SKM1 myeloid cell lines

Phenotypic and genotypic characterization of azacitidine-sensitive and resistant SKM1 myeloid cell lines

Activity of the selective IκB kinase inhibitor BMS-345541 against T-cell acute lymphoblastic leukemia

Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

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