scholarly journals Effects of FGFR Tyrosine Kinase Inhibition in OLN-93 Oligodendrocytes

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1318
Author(s):  
Ranjithkumar Rajendran ◽  
Gregor Böttiger ◽  
Niklas Dentzien ◽  
Vinothkumar Rajendran ◽  
Bischand Sharifi ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Severe Disease ◽  
Myelin Proteins ◽  
Signaling Cascades ◽  
Fgf Signaling ◽  
Fgfr Inhibition

Fibroblast growth factor (FGF) signaling is involved in the pathogenesis of multiple sclerosis (MS). Data from neuropathology studies suggest that FGF signaling contributes to the failure of remyelination in MS. In MOG35–55-induced EAE, oligodendrocyte-specific deletion of FGFR1 and FGFR2 resulted in a less severe disease course, reduced inflammation, myelin and axon degeneration and changed FGF/FGFR and BDNF/TrkB signaling. Since signaling cascades in oligodendrocytes could not be investigated in the EAE studies, we here aimed to characterize FGFR-dependent oligodendrocyte-specific signaling in vitro. FGFR inhibition was achieved by application of the multi-kinase-inhibitor dovitinib and the FGFR1/2/3-inhibitor AZD4547. Both substances are potent inhibitors of FGF signaling; they are effective in experimental tumor models and patients with malignancies. Effects of FGFR inhibition in oligodendrocytes were studied by immunofluorescence microscopy, protein and gene analyses. Application of the tyrosine kinase inhibitors reduced FGFR1, phosphorylated ERK and Akt expression, and it enhanced BDNF and TrkB expression. Furthermore, the myelin proteins CNPase and PLP were upregulated by FGFR inhibition. In summary, inhibition of FGFR signaling in oligodendrocytes can be achieved by application of tyrosine kinase inhibitors. Decreased phosphorylation of ERK and Akt is associated with an upregulation of BDNF/TrkB signaling, which may be responsible for the increased production of myelin proteins. Furthermore, these data suggest that application of FGFR inhibitors may have the potential to promote remyelination in the CNS.

Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics andin vitroCYP2C9 activity

2018 ◽  
Vol 25 (7) ◽  
pp. 1599-1607 ◽  
Author(s):  
Makoto Hiraide ◽  
Yuichi Minowa ◽  
Yasuhiro Nakano ◽  
Kenichi Suzuki ◽  
Taro Shiga ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
In Vitro Study ◽  
International Normalized Ratio ◽  
Bleeding Complications ◽  
Cytochrome P450 2C9

BackgroundElevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib.ObjectiveTo assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity.MethodsThis retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study.ResultsCompared with international normalized ratio at the baseline significant ( P < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing.ConclusionIn most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.

Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond

Hematology ◽  
2008 ◽  
Vol 2008 (1) ◽  
pp. 427-435 ◽  
Author(s):  
Junia V. Melo ◽  
Charles Chuah
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Novel Agents ◽  
Current Status ◽  
Genomic Amplification ◽  
Imatinib Resistance

AbstractThe emergence of resistance to imatinib has become a significant problem despite the remarkable clinical results achieved with this tyrosine kinase inhibitor in the treatment of chronic myeloid leukaemia. The most common cause of imatinib resistance is the selection of leukemic clones with point mutations in the Abl kinase domain. These mutations lead to amino acid substitutions and prevent the appropriate binding of imatinib. Genomic amplification of BCR-ABL, modulation of drug efflux or influx transporters, and Bcr-Abl–independent mechanisms also play important roles in the development of resistance. Persistent disease is another therapeutic challenge and may in part, be due to the inability of imatinib to eradicate primitive stem cell progenitors. A multitude of novel agents have been developed and have shown in vitro and in vivo efficacy in overcoming imatinib resistance. In this review, we will discuss the current status of the ATP-competitive and non-ATP–competitive Bcr-Abl tyrosine kinase inhibitors. We will also describe inhibitors acting on targets found in signaling pathways downstream of Bcr-Abl, such as the Ras-Raf-mitogen-activated protein kinase and phosphatidylinositol-3 kinase-Akt-mammalian target of rapamycin pathways, and targets without established links with Bcr-Abl.

scholarly journals Thrombotic microangiopathy in dasatinib-treated patients with chronic myeloid leukemia

2019 ◽  
Vol 4 (1-2) ◽  
pp. 41-45 ◽  
Author(s):  
Takeo Koshida ◽  
Sylvia Wu ◽  
Hitoshi Suzuki ◽  
Rimda Wanchoo ◽  
Vanesa Bijol ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Thrombotic Microangiopathy ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kidney Biopsy ◽  
Kinase Inhibitor ◽  
Target Effect

Dasatinib is the second-generation tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia. Proteinuria has been reported with this agent. We describe two kidney biopsy–proven cases of dasatinib-induced thrombotic microangiopathy that responded to stoppage of dasatinib and using an alternate tyrosine kinase inhibitor. Certain specific tyrosine kinase inhibitors lead to endothelial injury and renal-limited thrombotic microangiopathy. Hematologists and nephrologists need to be familiar with this off-target effect of dasatinib.

scholarly journals Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hu Lei ◽  
Han-Zhang Xu ◽  
Hui-Zhuang Shan ◽  
Meng Liu ◽  
Ying Lu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Tki Resistance

AbstractIdentifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.

In vitro UGT1A1 inhibition by tyrosine kinase inhibitors and association with drug-induced hyperbilirubinemia

2018 ◽  
Vol 82 (5) ◽  
pp. 795-802 ◽  
Author(s):  
Hisham Qosa ◽  
Brittany R. Avaritt ◽  
Neil R. Hartman ◽  
Donna A. Volpe
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Drug Induced

scholarly journals ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro

2013 ◽  
pp. 63 ◽  
Author(s):  
Karin Skoglund ◽  
Samuel Boiso Moreno ◽  
Maria Baytar ◽  
Jan Ingvar Jönsson ◽  
Henrik Gréen
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors

The patient with renal cell cancer

2015 ◽  
Author(s):  
Tim Eisen
Keyword(s):  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Renal Cancer ◽  
Renal Cell Cancer ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Cell Cancer

Renal cancer is the commonest malignancy of the kidney and worldwide, accounts for between 2% and 3% of the total cancer burden. The mainstay of curative treatment remains surgery. There have been significant advances in surgical technique, the most important ones being nephron-sparing surgery and laparoscopic nephrectomy. The medical treatment of advanced renal cell cancer has only improved markedly in the last decade with the development of antiangiogenic tyrosine-kinase inhibitors, inhibitors of mammalian target of rapamycin, and a diminished role for immunotherapy.Tyrosine-kinase inhibitor therapy results in reduction of tumour volume in around three-quarters of patients and doubles progression-free survival, but treatment is not curative. The management of side effects in patients on maintenance tyrosine-kinase inhibitors has improved in the last 3 years, although still presents difficulties which have to be actively considered.The molecular biology of renal cell carcinoma is better understood than for the majority of solid tumours. The commonest form of renal cancer, clear-cell carcinoma of the kidney, is strongly associated with mutations in the von Hippel–Lindau gene and more recently with chromatin-remodelling genes such as PBRM1. These genetic abnormalities lead to a loss of control of angiogenesis and uncontrolled proliferation of tumour cells. There is a very wide spectrum of tumour behaviour from the extremely indolent to the terribly aggressive. It is not currently known what accounts for this disparity in tumour behaviour.A number of outstanding questions are being addressed in scientific and clinical studies such as a clearer understanding of prognostic and predictive molecular biomarkers, the role of adjuvant therapy, the role of surgery in the presence of metastatic disease, how best to use our existing agents, and investigation of novel targets and therapeutic agents, especially novel immunotherapies.

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