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; Marisa L. Martin-Fernandez

doi:10.1038/s41467-024-46284-x

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^*, Marisa L. Martin-Fernandez^*

^*Corresponding author for this work

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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.

Original language	English
Article number	2130
Journal	Nature Communications
Volume	15
Issue number	1
Early online date	19 Mar 2024
DOIs	https://doi.org/10.1038/s41467-024-46284-x
Publication status	Published - Dec 2024

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Iyer, R. S., Needham, S. R., Galdadas, I., Davis, B. M., Roberts, S. K., Man, R. C. H., Zanetti-Domingues, L. C., Clarke, D. T., Fruhwirth, G. O., Parker, P. J., Rolfe, D. J., Gervasio, F. L., & Martin-Fernandez, M. L. (2024). Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers. Nature Communications, 15(1), Article 2130. https://doi.org/10.1038/s41467-024-46284-x

@article{df5dc46960e84233a753d7e98a6ff62f,

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

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.",

author = "Iyer, {R. Sumanth} and Needham, {Sarah R.} and Ioannis Galdadas and Davis, {Benjamin M.} and Roberts, {Selene K.} and Man, {Rico C H} and Zanetti-Domingues, {Laura C.} and Clarke, {David T.} and Fruhwirth, {Gilbert O.} and Parker, {Peter J.} and Rolfe, {Daniel J.} and Gervasio, {Francesco L.} and Martin-Fernandez, {Marisa L.}",

note = "Funding Information: We thank Drs Esther Garcia-Gonzalez, Jana Harizanova, Christopher Tynan, Michael Hirsch, Jianguo Rao and Michalis Vrettas for technical support. We thank James Rosekilly and Dr Cheryl Gillett for providing the human tissue TMA that consisted of no/low/high human cancer tissues. We thank Prof Andrew Clayton for his support in collecting the pbICS data. We also thank Dr Michael Hirsch for comments on the manuscript. This work has been funded by grant Ref: ST/S000682/1 from the Science and Technology Facilities Council UK (R.S.I. and B.M.D.) and a joint-funded King{\textquoteright}s College London-The University of Hong Kong PhD studentship (R.C.H.M.). M.L.M.-F., D.J.R., and B.M.D. are grateful for significant computing resources and support provided by STFC Scientific Computing Department{\textquoteright}s SCARF cluster and its Data Services, Research Infrastructure and Cloud Operations Groups, with funding from STFC{\textquoteright}s Ada Lovelace Centre and IRIS eInfrastructure consortium. F.L.G. and I.G. acknowledge the Swiss National Science Foundation and Bridge for financial support (project number: 200021_204795 and 40B2-0_203628). F.L.G. and I.G. also acknowledge the Swiss National Supercomputing Centre (CSCS) for large supercomputer time allocations, project IDs: s1107, s1169, s1228. Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-46284-x",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Iyer, RS, Needham, SR, Galdadas, I, Davis, BM, Roberts, SK, Man, RCH, Zanetti-Domingues, LC, Clarke, DT, Fruhwirth, GO, Parker, PJ, Rolfe, DJ, Gervasio, FL & Martin-Fernandez, ML 2024, 'Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers', Nature Communications, vol. 15, no. 1, 2130. https://doi.org/10.1038/s41467-024-46284-x

TY - JOUR

T1 - Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers

AU - Iyer, R. Sumanth

AU - Needham, Sarah R.

AU - Galdadas, Ioannis

AU - Davis, Benjamin M.

AU - Roberts, Selene K.

AU - Man, Rico C H

AU - Zanetti-Domingues, Laura C.

AU - Clarke, David T.

AU - Fruhwirth, Gilbert O.

AU - Parker, Peter J.

AU - Rolfe, Daniel J.

AU - Gervasio, Francesco L.

AU - Martin-Fernandez, Marisa L.

N1 - Funding Information: We thank Drs Esther Garcia-Gonzalez, Jana Harizanova, Christopher Tynan, Michael Hirsch, Jianguo Rao and Michalis Vrettas for technical support. We thank James Rosekilly and Dr Cheryl Gillett for providing the human tissue TMA that consisted of no/low/high human cancer tissues. We thank Prof Andrew Clayton for his support in collecting the pbICS data. We also thank Dr Michael Hirsch for comments on the manuscript. This work has been funded by grant Ref: ST/S000682/1 from the Science and Technology Facilities Council UK (R.S.I. and B.M.D.) and a joint-funded King’s College London-The University of Hong Kong PhD studentship (R.C.H.M.). M.L.M.-F., D.J.R., and B.M.D. are grateful for significant computing resources and support provided by STFC Scientific Computing Department’s SCARF cluster and its Data Services, Research Infrastructure and Cloud Operations Groups, with funding from STFC’s Ada Lovelace Centre and IRIS eInfrastructure consortium. F.L.G. and I.G. acknowledge the Swiss National Science Foundation and Bridge for financial support (project number: 200021_204795 and 40B2-0_203628). F.L.G. and I.G. also acknowledge the Swiss National Supercomputing Centre (CSCS) for large supercomputer time allocations, project IDs: s1107, s1169, s1228. Publisher Copyright: © The Author(s) 2024.

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-024-46284-x

DO - 10.1038/s41467-024-46284-x

M3 - Article

C2 - 38503739

AN - SCOPUS:85188066800

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2130

ER -

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

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