Disrupting aberrant EGFR catalytic trimers reverses T790M gefitinib resistance

Abstract

Epidermal growth factor receptor (EGFR) mutations drive up to 50% of non-small-cell lung cancers (NSCLC). Although tyrosine kinase inhibitors provide substantial clinical benefit, remissions are prematurely terminated by the inevitable acquisition of on-target resistance. Beyond structural changes that alter ATP-pocket affinity, EGFR oligomerization drives this resistance, though the underlying mechanisms remain unclear. Here we show that progressive secondary and tertiary resistant NSCLC EGFR-mutants form ligand-free cell surface oligomers that contain catalytic trimers instead of the canonical dimers found within these oligomers in wild-type and gefitinib-sensitive EGFR-mutants. 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 normal tumor growth. These findings reveal a structural vulnerability specific to these refractory variants, demonstrating that targeting intra-oligomer interactions can overcome resistance, and providing a blueprint for protein-protein interface modulation strategies in NSCLC.