Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers

R. Sumanth Iyer, Sarah R. Needham, Ioannis Galdadas, Benjamin M. Davis, Selene K. Roberts, Rico C. H. Man, Laura C. Zanetti-Domingues, David T. Clarke, Gilbert O. Fruhwirth, Peter J. Parker, Daniel J. Rolfe (), Francesco L. Gervasio () and Marisa L. Martin-Fernandez ()
Additional contact information
R. Sumanth Iyer: UKRI-STFC Rutherford Appleton Laboratory
Sarah R. Needham: UKRI-STFC Rutherford Appleton Laboratory
Ioannis Galdadas: University of Geneva
Benjamin M. Davis: UKRI-STFC Rutherford Appleton Laboratory
Selene K. Roberts: UKRI-STFC Rutherford Appleton Laboratory
Rico C. H. Man: School of Cancer and Pharmaceutical Sciences, Guy’s Campus, King’s College London
Laura C. Zanetti-Domingues: UKRI-STFC Rutherford Appleton Laboratory
David T. Clarke: UKRI-STFC Rutherford Appleton Laboratory
Gilbert O. Fruhwirth: School of Cancer and Pharmaceutical Sciences, Guy’s Campus, King’s College London
Peter J. Parker: The Francis Crick Institute
Daniel J. Rolfe: UKRI-STFC Rutherford Appleton Laboratory
Francesco L. Gervasio: University of Geneva
Marisa L. Martin-Fernandez: UKRI-STFC Rutherford Appleton Laboratory

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Oncogenic EGFR has been successfully targeted by tyrosine kinase inhibitors, but acquired drug resistance eventually overcomes the efficacy of these treatments. Attempts to surmount this therapeutic challenge are hindered by a poor understanding of how and why cancer mutations specifically amplify ligand-independent EGFR auto-phosphorylation signals to enhance cell survival and how this amplification is related to ligand-dependent cell proliferation. Here we show that drug-resistant EGFR mutations manipulate the assembly of ligand-free, kinase-active oligomers to promote and stabilize the assembly of oligomer-obligate active dimer sub-units and circumvent the need for ligand binding. We reveal the structure and assembly mechanisms of these ligand-free, kinase-active oligomers, uncovering oncogenic functions for hitherto orphan transmembrane and kinase interfaces, and for the ectodomain tethered conformation of EGFR. Importantly, we find that the active dimer sub-units within ligand-free oligomers are the high affinity binding sites competent to bind physiological ligand concentrations and thus drive tumor growth, revealing a link with tumor proliferation. Our findings provide a framework for future drug discovery directed at tackling oncogenic EGFR mutations by disabling oligomer-assembling interactions.

Date: 2024
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DOI: 10.1038/s41467-024-46284-x

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