EGFR and tyrosine kinase inhibitor interactions probed by hydrogen-deuterium exchange and mass spectrometry (HDX-MS)
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EGFR is one of the primary drug targets for treating non-small cell lung cancer (NSCLC) patients carrying EGFR oncogenic mutations in the tyrosine kinase domain (TKD). Such patients typically receive tyrosine kinase inhibitors (TKIs) to inhibit aberrant activation of EGFR; however, together with the appearance of the TKI-resistant mutations, TKIs’ severe side effects often limit their clinical usage. To develop TKIs with the wild-type sparing effect, the wild-type structures bound to various TKIs ought to be characterized, though comparisons of such crystal structures do not show clear differences. To characterize subtle EGFR TKD structural changes upon TKI binding that cannot be gleaned from crystal structure comparisons, we employed HDX-MS. We show inhibitor-dependent EGFR dynamics that are displayed even among the TKD bound to chemically similar inhibitors. Such inhibitor-dependent structural changes appear to underlie TKI side effects and the selectivity of covalent inhibitors.
Highlights
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EGFR shows TKI-dependent dynamics even if TKIs are structurally similar.
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The stability of the TKI-encounter complexes correlates with their side effects.
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Covalent TKIs disrupt the binding pocket of wild-type EGFR.
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The structure of the osimertinib-L858R/T790M complex is extremely rigid.
