Targeting the NRG1/HER3 axis to overcome therapy resistance in head and neck squamous cell carcinoma: Insights from patient-derived xenografts.

e18056 Background: Epidermal growth factor receptor is frequently overexpressed in head and neck squamous cell carcinoma and is associated with poor clinical outcomes. Cetuximab, an approved anti-EGFR monoclonal antibody, yields modest (10–30%) and often non-durable responses due to intrinsic and acquired resistance. Compensatory signaling through other ERBB receptors, including HER3, has been proposed as a bypass mechanism. We aimed to investigate EGFR-family signaling features associated with cetuximab response and resistance using patient-derived xenografts. Methods: A characterized panel of HNSCC PDXs was established. Palpable tumors were cryopreserved and expanded for in vivo cetuximab testing and ex vivo profiling. PDX fidelity to matched patient tumors was assessed by immunohistochemistry. Molecular and proteomic characterization included next-generation sequencing (NGS), Western blotting to evaluate EGFR-family expression and heterodimer distribution. Results: All PDXs recapitulated key morphological and functional traits of the corresponding patient tumors by IHC. Integrated profiling (NGS/Western blot) identified distinct EGFR-related signatures, heterogeneous EGFR-family protein expression, and variable heterodimer patterns across models. These features paralleled differential in vivo sensitivity to cetuximab. In an HPV-negative PDX model, tumors progressing under cetuximab displayed increased expression of EGFR-family members, particularly HER2 and HER3, compared with cetuximab-responsive tumors. Conclusions: Characterized HNSCC PDXs capture clinically relevant heterogeneity and reveal EGFR-family remodeling associated with variable cetuximab response. This platform may help identify HNSCC subgroups for rational combinations incorporating emerging anti-HER3 strategies (e.g., bispecific antibodies, antibody–drug conjugates, or aptamers) to limit compensatory signaling and improve cetuximab efficacy.