Fassunke, Jana, Mueller, Fabienne, Keul, Marina, Michels, Sebastian, Dammert, Marcel A., Schmitt, Anna, Plenker, Dennis, Lategahn, Jonas ORCID: 0000-0001-5993-7082, Heydt, Carina, Braegelmann, Johannes, Tumbrink, Hannah L., Alber, Yannic, Klein, Sebastian, Heimsoeth, Alena, Dahmen, Ilona, Fischers, Rieke N., Scheffler, Matthias, Ihle, Michaela A., Priesner, Vanessa, Scheel, Andreas H., Wagener, Svenja, Kron, Anna, Frank, Konrad, Garbert, Katia, Persigehl, Thorsten, Puesken, Michael, Haneder, Stefan, Schaaf, Bernhard, Rodermann, Ernst, Engel-Riedel, Walburga, Felip, Enriqueta, Smit, Egbert F., Merkelbach-Bruse, Sabine, Reinhardt, H. Christian, Kast, Stefan M., Wolf, Juergen, Rauh, Daniel, Buettner, Reinhard and Sos, Martin L. (2018). Overcoming EGFR(G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors. Nat. Commun., 9. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Fassunke, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, FabienneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keul, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michels, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dammert, Marcel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plenker, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lategahn, JonasUNSPECIFIEDorcid.org/0000-0001-5993-7082UNSPECIFIED
Heydt, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braegelmann, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tumbrink, Hannah L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alber, YannicUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heimsoeth, AlenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dahmen, IlonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischers, Rieke N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffler, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ihle, Michaela A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Priesner, VanessaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheel, Andreas H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagener, SvenjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kron, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frank, KonradUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garbert, KatiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Puesken, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haneder, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaaf, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodermann, ErnstUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel-Riedel, WalburgaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Felip, EnriquetaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smit, Egbert F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkelbach-Bruse, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kast, Stefan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-165948
DOI: 10.1038/s41467-018-07078-0
Journal or Publication Title: Nat. Commun.
Volume: 9
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL LUNG-CANCER; ACQUIRED-RESISTANCE; GENETIC ALTERATIONS; KINASE DOMAIN; MUTATIONS; GEFITINIB; AZD9291; T790M; ACTIVATION; MECHANISMSMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16594

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