2020-06-01
Mutation and drug-specific intracellular accumulation of EGFR predict clinical responses to tyrosine kinase inhibitors
Publication
Publication
EBioMedicine , Volume 56
Background: Clinical responses to EGFR tyrosine kinase inhibitors (TKIs) are restricted to tumors harboring specific activating mutations and even then, not all tyrosine kinase inhibitors provide clinical benefit. All TKIs however, effectively inhibit EGFR phosphorylation regardless of the mutation present. Methods: High-throughput, high-content imaging analysis, western blot, Reversed phase protein arrays, mass spectrometry and RT-qPCR. Findings: We show that the addition of TKIs results in a strong and rapid intracellular accumulation of EGFR. This accumulation mimicked clinical efficacy as it was observed only in the context of the combination of a TKI-sensitive mutation with a clinically effective (type I) TKI. Intracellular accumulation of EGFR was able to predict response to gefitinib in a panel of cell-lines with different EGFR mutations. Our assay also predicted clinical benefit to EGFR TKIs on a cohort of pulmonary adenocarcinoma patients (hazard ratio 0.21, P=0.0004 [Cox proportional hazard model]) and could predict the clinical response in patients harboring rare mutations with unknown TKI-sensitivity. All investigated TKIs, regardless of clinical efficacy, inhibited EGFR phosphorylation and downstream pathway activation, irrespective of the mutation present. Intracellular accumulation of EGFR depended on a continued presence of TKI indicating (type I) TKIs remain associated with the protein even after its dephosphorylation. Accumulation therefore is likely caused by two consecutive conformational changes, induced by both activating mutation and TKI, that combined block EGFR-membrane recycling. Interpretation: We report on an assay that mimics the discrepancy between molecular and clinical activity of EGFR-TKIs, which may allow response prediction in vitro and helps understand the mechanism of effective inhibitors.
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| doi.org/10.1016/j.ebiom.2020.102796, hdl.handle.net/1765/127725 | |
| EBioMedicine | |
| Organisation | Department of Neurology |
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de Wit, M. (Maurice), Gao, Y., Mercieca, D. (Darlene), de Heer, I. (Iris), Valkenburg, B. (Bart), Royen, M., … French, P. (2020). Mutation and drug-specific intracellular accumulation of EGFR predict clinical responses to tyrosine kinase inhibitors. EBioMedicine, 56. doi:10.1016/j.ebiom.2020.102796 |
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