Label-free cell phenotypic assessment of the molecular mechanism of action of epidermal growth factor receptor inhibitors

摘要: Epidermal growth factor receptor (EGFR) is the target of several clinically approved tyrosine kinase inhibitor (TKI) drugs including gefitinib and erlotinib in treatment cancer. Multiple mechanisms have been implicated clinical features these drugs. However, little known about molecular mechanism action at whole cell level. Here we applied a label-free biosensor-enabled dynamic mass redistribution (DMR) assay to assess three EGFR inhibitors, gefitinib, AG1478, alter signaling A431 HT-29, two native cancer lines expressing EGFR. The whole-cell DMR assays with persistent showed that all inhibitors dose-dependently inhibited both lines, but generally displayed higher potency than HT-29 cells. washout unexpectedly increased AG-1478 inhibit A431, slightly decreased HT29. under microfluidics removal using buffer perfusion resulted time-dependent recovery EGF slower In contrast, reversible competitive antagonists led full signalling distinct G protein-coupled receptors (GPCRs), β2-adrenergic GPR35 Together, our results suggest for their uptake retention, rather binding kinetics, dominate phenotypic efficacy; however, GPCR characteristics are critical inhibitory effects. This study also implicates potential different simulation conditions elucidating pharmacology, particular transporter-related drug resistance,