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

著者 Fassunke J , Müller F , Keul M , Michels S , Dammert MA , Schmitt A , Plenker D , Lategahn J , Heydt C , Brägelmann J , Tumbrink HL , Alber Y , Klein S , Heimsoeth A , Dahmen I , Fischer RN , Scheffler M , Ihle MA , Priesner V , Scheel AH , Wagener S , Kr
Nat Commun.2018 Nov 07 ; 9(1):4655.
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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-negative but EGFR-positive subclones and osimertinib resistance. We demonstrate that EGFR limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFR 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 affinity and overcome EGFR-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFR-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFR-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.
PMID: 30405134 [PubMed - in process]
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