scholarly journals Subcellular localization of several structurally different tyrosine kinase inhibitors

ADMET & DMPK ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 258-266 ◽  
Author(s):  
Richard Honeywell ◽  
Sarina Hitzerd ◽  
Ietje Kathmann ◽  
Godefridus Peters
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Similar Distribution ◽  
Lysosomal Accumulation ◽  
Vegfr Inhibitor ◽  
General Localization

Protein tyrosine kinases form an important target for a new class of anticancer drugs, the tyrosine kinase inhibitors (TKIs). Recently we demonstrated that sunitinib, an inhibitor of the membrane-associated vascular endothelial growth factor receptor (VEGFR), is trapped in lysosomes which isolates the drug from its intended target. Therefore we investigated whether this also holds for other TKIs, targeted against different protein kinases. For this purpose we used the ProteoExtractR kit, which enables a subcellular extraction separating cellular proteins into four distinct fractions covering the cytosol, membranes and membrane organelles (including lysosomes), nuclear proteins and the cytoskeleton. Since TKIs are 98-100 % protein bound we used this property to study their subcellular distribution and used Caco-2 cells as a model. As expected after 2 hours exposure sunitinib was trapped in cytosol (58 %) and organelles (42 % including lysosomes). Crizotinib, an inhibitor of ALK-EML4, showed a similar distribution. However, erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR) showed a very low cellular accumulation and was limited to the organelle fraction. In contrast, the other EGFR inhibitor, gefitinib was predominantly located in the cytosolic (39 %) and membrane fraction (44 %). Sorafenib, another VEGFR inhibitor was predominantly located in the organelle fraction (85 %) and cytosol (15 %) after 2 hours, while after 24 hours distribution decreased (9.9 fold) with a slight shift. Dasatinib, an inhibitor of BCR-Abl was located only in the cytosol (100 %). In general localization after 24 hours was comparable, albeit several small changes were seen. In conclusion protein fractionation with the ProteoExtractR Subcellular Proteome Extraction kit demonstrated large differences in TKI levels in various cellular organelles, with a pattern in agreement with lysosomal accumulation of sunitinib.

scholarly journals Tyrosine Kinase Inhibitors in Adult Glioblastoma: An (Un)Closed Chapter?

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5799
Author(s):  
Paula Aldaz ◽  
Imanol Arozarena
Keyword(s):  
Clinical Trials ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Growth Factor Receptor ◽  
Medical Community ◽  
Molecular Events

Glioblastoma (GBM) is the most common and lethal form of malignant brain tumor. GBM patients normally undergo surgery plus adjuvant radiotherapy followed by chemotherapy. Numerous studies into the molecular events driving GBM highlight the central role played by the Epidermal Growth Factor Receptor (EGFR), as well as the Platelet-derived Growth Factor Receptors PDGFRA and PDGFRB in tumor initiation and progression. Despite strong preclinical evidence for the therapeutic potential of tyrosine kinase inhibitors (TKIs) that target EGFR, PDGFRs, and other tyrosine kinases, clinical trials performed during the last 20 years have not led to the desired therapeutic breakthrough for GBM patients. While clinical trials are still ongoing, in the medical community there is the perception of TKIs as a lost opportunity in the fight against GBM. In this article, we review the scientific rationale for the use of TKIs targeting glioma drivers. We critically analyze the potential causes for the failure of TKIs in the treatment of GBM, and we propose alternative approaches to the clinical evaluation of TKIs in GBM patients.

scholarly journals Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-small cell lung cancer

2015 ◽  
Vol 3 (02) ◽  
pp. 81-87
Author(s):  
Lawaly Maman Manzo ◽  
Moudirat Lawaly ◽  
Lui YU
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Endothelial Growth Factor ◽  
Receptor Tyrosine Kinase Inhibitors

Aberrant increased expression and activation of receptor tyrosine kinases occur frequently in human carcinomas. Several small molecules targeting receptor tyrosine kinases, which have crucial roles in the growth factor signaling that promote tumor progression in various malignancies, including non-small cell lung cancer (NSCLC), are currently in clinical development. Therapeutic strategies include inhibition of growth factor tyrosine kinase function. Drugs of this type include those that target the epidermal growth factor receptor tyrosine kinase, those that target vascular endothelial growth factor receptors tyrosine kinase and those that target anaplastic lymphoma receptor tyrosine kinase. In this review we first discuss the role of receptor tyrosine kinases in human malignancies, and focus on discussing the potential use of epidermal growth factor receptor tyrosine kinase inhibitors and the vascular endothelial growth factor receptors tyrosine kinase inhibitors in NSCLC. In addition, we discuss the contribution of growth factor receptor tyrosine kinase inhibitors to the clinically observed resistance, and toxicity.

scholarly journals Efficacy of Next-Generation EGFR-TKIs in Patients With Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials

2020 ◽  
Vol 19 ◽  
pp. 153303382094042
Author(s):  
Yi-Tian Qi ◽  
Yi Hou ◽  
Liang-Chen Qi
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Receptor Tyrosine Kinase Inhibitors

Background: The efficacy of next-generation epidermal growth factor receptor-tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer who have failed first-generation epidermal growth factor receptor-tyrosine kinase inhibitors still remains under investigation. Objective: The aim of this meta-analysis was to systematically assess the efficacy and safety profiles of next-generation epidermal growth factor receptor-tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer who failed first-generation epidermal growth factor receptor-tyrosine kinase inhibitors. Methods: We performed a comprehensive search of several electronic databases up to September 2018 to identify clinical trials. The primary end point was overall survival, progression-free survival, disease controlled rate, objective response rate, and adverse events. Epidermal growth factor receptor-tyrosine kinase inhibitor emergent severe adverse events (grade ≥ 3) were analyzed. Odds ratio along with 95% confidence interval were utilized for main outcome analysis. Results: In total, we had 3 randomized controlled trials in this analysis. The group of next-generation epidermal growth factor receptor-tyrosine kinase inhibitors had significantly improved progression-free survival (odds ratio = 0.34, 95% confidence interval = 0.29-0.40, P < .00001), as well as objective response rate (odds ratio = 10.48, 95% confidence interval = 3.87-28.34, P < .00001) and disease controlled rate (odds ratio = 6.03, 95% confidence interval = 4.41-8.25, P < .00001). However, there was no significant difference in overall survival with next-generation epidermal growth factor receptor-tyrosine kinase inhibitors (odds ratio = 1.05, 95% confidence interval = 0.85-1.31, P = .66). Meanwhile, the odds ratio for treatment-emergent severe adverse events (diarrhea, rash/acne, nausea, vomiting, anemia) between patients who received next-generation epidermal growth factor receptor-tyrosine kinase inhibitors and those who received first-generation epidermal growth factor receptor-tyrosine kinase inhibitors did not show safety benefit ( P > .05). Conclusions: Next-generation epidermal growth factor receptor-tyrosine kinase inhibitors were shown to be the better agent to achieve higher response rate and longer progression-free survival in patients with non-small cell lung cancer as the later-line therapy for previously treated patients with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors. Meanwhile, they did not achieve benefit in overall survival and safety compared with the chemotherapy group. Further research is needed to develop a database of all EGFR mutations and their individual impacts on the various treatments.

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