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

Nat Commun 2018 11 7;9(1):4655. Epub 2018 Nov 7.

Molecular Pathology, Institute of Pathology, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

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.

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http://www.nature.com/articles/s41467-018-07078-0
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http://dx.doi.org/10.1038/s41467-018-07078-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220297PMC
November 2018
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