Abstract
Erlotinib and gefitinib, tyrosine kinase inhibitors used to block EGFR (epidermal growth factor receptor) signalling in cancer, are thought to bind only the active conformation of the EGFR-TKD (tyrosine kinase domain). Through parallel computational and crystallographic studies, we show in the present study that erlotinib also binds the inactive EGFR-TKD conformation, which may have significant implications for its use in EGFR-mutated cancers.
Highlights
Activating mutations in the epidermal growth factor receptor (EGFR) are well accepted as oncogenic drivers in such cancers as non-small-cell lung cancer (NSCLC) [1] and glioblastoma [2,3]
EGFR activated by tyrosine kinase domain (TKD) mutations in NSCLC can be inhibited by erlotinib and CI-1033 but not by lapatinib or HKI-272, whereas the same receptor activated by extracellular mutations in glioblastoma is inhibited by lapatinib and HKI-272 but not by erlotinib or CI-1033 [3]
It is generally assumed that the EGFR inhibitors gefitinib and erlotinib bind selectively to the active conformation of EGFR-TKD, whereas lapatinib selectively binds the inactive configuration
Summary
Activating mutations in the EGFR (epidermal growth factor receptor) are well accepted as oncogenic drivers in such cancers as NSCLC (non-small-cell lung cancer) [1] and glioblastoma [2,3]. Docking erlotinib on to wild-type EGFR-TKD in its active conformation, as described, closely reproduced the binding mode observed crystallographically in PDB entry 1M17 [10] As described in the text, the crystal structure shown in (A) confirms our computational findings that erlotinib can bind to the inactive EGFR-TKD conformation.
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