Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-07078-0
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Funding
- Deutsche Forschungsgemeinschaft [KFO-286/RP2, RE 2246/2-1, RE 2246/7-1]
- Bundesministerium fur Bildung und Forschung [e: Med 01ZX1303A, 01ZX1406]
- German federal state North Rhine Westphalia (NRW) as part of the EFRE initiative [LS-1-1-030a]
- Else KronerFresenius Stiftung [EKFS-2014-A06, 2016_ Kolleg.19]
- Deutsche Krebshilfe [111724]
- Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program
- Deutsche Forschungsgemeinschaft (DFG)
- German federal state North RhineWestphalia (NRW)
- European Union (European Regional Development Fund: Investing In Your Future) [EFRE-800400]
- NEGECA (PerMed NRW)
- EMODI
- German Federal Ministry for Education and Research (NGFNPlus) [BMBF 01GS08104, 01ZX1303C]
- German Federal Ministry for Education and Research (e: Med) [BMBF 01GS08104, 01ZX1303C]
- Deutsche Forschungsgemeinschaft (Cluster of Excellence RESOLV EXC 1069)
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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(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 affinity and overcome EGFR(G724S)-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFR(G724S)-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFR(G724S)-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.
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