Transport of six tyrosine kinase inhibitors: active or passive?

<p class="ADMETabstracttext">Transport of erlotinib, gefitinib, sorafenib, sunitinib, dasatinib and crizotinib can be active or passive, which was studied by measuring uptake at low (4 °C; passive) and normal temperature (37 °C; active and passive) and by the use of specific organic cation transporter (OCT) inhibitors. Intracellular accumulation was determined using Caco-2 as monolayers, while for gut permeation we used differentiated Caco-2 as model for intestinal epithelium in the Transwell system. Sorafenib and crizotinib uptake are likely to be dependent on passive transport. Gefitinib, dasatinib and sunitinib uptake seem to be active. Erlotinib’s transport also seems to be active. This study suggests that hOCTs might be involved in the apical to basolateral transport of gefitinib and crizotinib. Overall it can be concluded that the accumulation and transport of these six TKIs are very different, despite the fact that they are all tyrosine kinase inhibitors.</p>

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Inhibition of organic cation transporter 3 activity by tyrosine kinase inhibitors

Fundamental and Clinical Pharmacology ◽

10.1111/fcp.12657 ◽

2021 ◽

Author(s):

Karima Alim ◽

Amélie Moreau ◽

Arnaud Bruyère ◽

Elodie Jouan ◽

Claire Denizot ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Organic Cation ◽

Organic Cation Transporter ◽

Organic Cation Transporter 3

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Interactions of Tyrosine Kinase Inhibitors with Organic Cation Transporters and Multidrug and Toxic Compound Extrusion Proteins

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-10-0731 ◽

2011 ◽

Vol 10 (3) ◽

pp. 531-539 ◽

Cited By ~ 117

Author(s):

Tsuyoshi Minematsu ◽

Kathleen M. Giacomini

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Organic Cation ◽

Organic Cation Transporters ◽

Toxic Compound ◽

Cation Transporters

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Effective Tyrosine Kinase Inhibitors result in the intracellular accumulation of EGFR and allows response prediction in patients

10.1101/798314 ◽

2019 ◽

Author(s):

Maurice de Wit ◽

Ya Gao ◽

Darlene Mercieca ◽

Iris de Heer ◽

Bart Valkenburg ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Conformational Changes ◽

Clinical Benefit ◽

Kinase Inhibitors ◽

Response Prediction ◽

Egfr Mutations ◽

Tumor Type ◽

Intracellular Accumulation ◽

Egfr Tkis

AbstractClinical responses to EGFR tyrosine kinase inhibitors are restricted only to tumors harboring specific activating mutations and even then, not all tyrosine kinase inhibitors provide clinical benefit. We here show that the addition of EGFR-TKIs results in a strong and rapid intracellular accumulation of the protein. However, this accumulation was observed only in the context of a combination of a TKI-sensitive mutation with a clinically effective TKI: TKI-insensitive mutations did not show this accumulation nor did clinically ineffective TKIs induce accumulation. All TKIs effectively inhibited EGFR phosphorylation and downstream pathway activation, irrespective of the mutation present in EGFR. The discrepancy between molecular activity of TKIs and their efficacy in patients therefore is mimicked by the mutation- and TKI-specificity of intracellular accumulation. Using this intracellular accumulation as assay, we were able to predict response to gefitinib in a panel of cell-lines (harboring different EGFR mutations) and predicted clinical benefit to EGFR TKIs on a cohort of unselected pulmonary adenocarcinoma patients (hazard ratio 0.21, P=0.0004). Even in patients harboring rare mutations with unknown TKI-sensitivity, intracellular accumulation was predictive of the clinical response. The intracellular accumulation depended on a continued presence of TKI indicating that TKIs exert a continued effect on the protein even after its dephosphorylation. It is therefore possible that accumulation is caused by conformational changes induced by both the mutation and the TKI and this change induces a block in intracellular trafficking. Interestingly, intracellular accumulation was observed independent of the genetic background of the cell, indicating that accumulation is almost entirely dictated by the combination of mutation and TKI. Our results therefore suggest that TKI-sensitivity is tumor-type independent.

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