Structural Insights into Characterizing Binding Sites in Epidermal Growth Factor Receptor Kinase Mutants

Over
the last two decades epidermal growth factor receptor (EGFR)
kinase has become an important target to treat nonsmall cell lung
cancer (NSCLC). Currently, three generations of EGFR kinase-targeted
small molecule drugs have been FDA approved. They nominally produce
a response at the start of treatment and lead to a substantial survival
benefit for patients. However, long-term treatment results in acquired
drug resistance and further vulnerability to NSCLC. Therefore, novel
EGFR kinase inhibitors that specially overcome acquired mutations
are urgently needed. To this end, we carried out a comprehensive study
of different EGFR kinase mutants using a structural systems pharmacology
strategy. Our analysis shows that both wild-type and mutated structures
exhibit multiple conformational states that have not been observed
in solved crystal structures. We show that this conformational flexibility
accommodates diverse types of ligands with multiple types of binding
modes. These results provide insights for designing a new generation
of EGFR kinase inhibitor that combats acquired drug-resistant mutations
through a multiconformation-based drug design strategy.