Disrupting aberrant EGFR catalytic trimers reverses T790M gefitinib resistance
- 1Central Laser Facility, UKRI-STFC Rutherford Appleton Laboratory, Didcot, Oxfordshire, UK
Abstract
Epidermal growth factor receptor (EGFR) mutations drive up to 50% of non-small-cell lung cancers (NSCLC). Although tyrosine kinase inhibitors (TKIs) like gefitinib initially offer substantial clinical benefit, the emergence of acquired, on-target resistance inevitably limits long-term remission. Beyond structural changes that alter ATP-pocket affinity, EGFR oligomerization drives this resistance, though the underlying mechanisms remain unclear. Here we show that progressive, TKI-resistant secondary and tertiary EGFR-mutant variants assemble on the cell surface into higher-order, ligand-free oligomers organized around pathological catalytic trimers. In contrast, gefitinib-sensitive variants assemble into oligomers where the catalytic units remain as canonical dimers, like those found in wild-type oligomers. Genetically disrupting these pathological trimers into dimers via a single-point mutation rewires downstream signaling, decelerates tumor progression, and reverses gefitinib resistance in vivo. Conversely, genetic engineering of dimers into trimers reinstates aggressive tumor growth. These findings expose a structural vulnerability unique to acquired mutations, demonstrating that selectively targeting these pathological intra-oligomer trimers can overcome resistance, and provide a blueprint for protein-protein interface modulation strategies that spare wild-type signaling.
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BibTeX
@misc{roberts2026disrupting,
title = {{Disrupting aberrant EGFR catalytic trimers reverses T790M gefitinib resistance}},
author = {S. K. Roberts and I. Galdadas and N. Piasentin and S. R. Needham and L. C. Zanetti-Domingues and B. M. Davis and R. C. H. Man and D. T. Clarke and A. H. A. Clayton and D. J. Rolfe and G. O. Fruhwirth and F. L. Gervasio and M. L. Martin-Fernandez},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.754095},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.754095v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Disrupting aberrant EGFR catalytic trimers reverses T790M gefitinib resistance
AU - S. K. Roberts
AU - I. Galdadas
AU - N. Piasentin
AU - S. R. Needham
AU - L. C. Zanetti-Domingues
AU - B. M. Davis
AU - R. C. H. Man
AU - D. T. Clarke
AU - A. H. A. Clayton
AU - D. J. Rolfe
AU - G. O. Fruhwirth
AU - F. L. Gervasio
AU - M. L. Martin-Fernandez
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.754095
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.754095v1
AB - Epidermal growth factor receptor (EGFR) mutations drive up to 50% of non-small-cell lung cancers (NSCLC). Although tyrosine kinase inhibitors (TKIs) like gefitinib initially offer substantial clinical benefit, the emergence of acquired, on-target resistance inevitably limits long-term remission. Beyond structural changes that alter ATP-pocket affinity, EGFR oligomerization drives this resistance, though the underlying mechanisms remain unclear. Here we show that progressive, TKI-resistant secondary and tertiary EGFR-mutant variants assemble on the cell surface into higher-order, ligand-free oligomers organized around pathological catalytic trimers. In contrast, gefitinib-sensitive variants assemble into oligomers where the catalytic units remain as canonical dimers, like those found in wild-type oligomers. Genetically disrupting these pathological trimers into dimers via a single-point mutation rewires downstream signaling, decelerates tumor progression, and reverses gefitinib resistance in vivo. Conversely, genetic engineering of dimers into trimers reinstates aggressive tumor growth. These findings expose a structural vulnerability unique to acquired mutations, demonstrating that selectively targeting these pathological intra-oligomer trimers can overcome resistance, and provide a blueprint for protein-protein interface modulation strategies that spare wild-type signaling.
ER -