NRG1/HER3 axis drives therapy resistance in head and neck squamous cell carcinoma: Evidence from patient-derived xenografts

Epidermal Growth Factor Receptor (EGFR) is commonly overexpressed and associated with poor clinical outcomes in Head and Neck Squamous Cell Carcinoma (HNSCC). Indeed, the EGFR monoclonal antibody, Cetuximab (CTX) has been the first FDA-approved targeted drug but demonstrating limited (10-30%) and not durable response due to both intrinsic and acquired resistance mechanisms. Data from our in vitro experiments, and confirmed by the literature, showed an increased HER3 protein level after cetuximab treatment in HNSCC 2D cell lines, suggesting that this receptor may represent a bypass pathway to anti-EGFR therapy . However, given the complexity of HNSCC, characterized by different etiology, anatomical sites and high inter- and intratumoral heterogeneity, we focused our research study on a more representative model establishing a small set of characterized patient-derived xenografts (PDXs). Palpable tumors were cryopreserved and expanded for drug testing and ex vivo characterization. Immunohistochemistry analysis revealed that all the established PDX models recapitulate morphological and functional traits of the corresponding patient tumors. While, NGS, Western Blots and QF-PRO®, a FRET-FLIM based technic, identified distinct EGFR signature, protein expression and heterodimers distribution across samples. These results reflected a differential response to anti-EGFR blockade in vivo . Moreover, analysis conducted in one PDX model, derived from HPV negative sample, showed high expression of EGFR family members, HER2 and HER3, when tumors are no more responding to CTX treatment.In conclusion, characterized PDX models will help to identify HNSCC subgroups that may benefit to a combinatorial approach using anti-HER3 innovative drugs, like bispecific antibodies, antibody-drug conjugates or aptamers, to bypass compensatory signaling pathway and improve CTX sensitivity.