Overcoming EGFR^G724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors.

ABSTRACT: The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFR^T790M-negative but EGFR^G724S-positive subclones and osimertinib resistance. We demonstrate that EGFR^G724S limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFR^G724S mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinit

SUBMITTER: Fassunke J 

PROVIDER: S-EPMC6220297 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature