Neuroendocrine-like/EMT dedifferentiation mediates resistance to EGFR inhibitors via the NRG1/HER3 axis

Patients with non-small cell lung cancer (NSCLC) carrying activating EGFR mutations typically respond favorably to third-generation EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib. Nevertheless, resistance almost inevitably emerges, ultimately limiting the durability of these treatments. We investigated non-genomic mechanisms enabling drug-tolerant persister cells to survive EGFR inhibition, likely co-opting compensatory HER3 activation, whose underlying mechanisms remain unclear. Using a combination of immortalized and patient-derived cellular models, together with single-cell RNA sequencing, we demonstrate that activation of EGFR/HER3 axis constitutes an early adaptive response to TKI exposure enriched in pulmonary alveolar type I and type II cancer cells. This response is driven by neuregulin-1 (NRG1), produced by stromal cells and by cancer cells undergoing NE-like/EMT dedifferentiation. Importantly, in vivo studies demonstrated that combining EGFR inhibition and NRG1 neutralization by monoclonal antibody successfully eradicated tumors. Together, these findings point to a therapeutic strategy to overcome TKI resistance in NSCLC through targeting HER3 signalling, its interplay with EGFR, and tumor microenvironment–derived cues.