| Autor: |
Mascha Binder, Carsten Bokemeyer, Sonja Loges, Boris Fehse, Kristoffer Riecken, Rainald Knecht, Martin Trepel, Bruno Märkl, Elzbieta Jakubowicz, Steffen Goletz, Antje Danielczyk, Simon Laban, Ingke Braren, Isabel Ben Batalla, Anja Thalhammer, Markus Sack, Veronique Blanchard, Karina Biskup, Tobias Grob, Beate Habel, Minna Voigtlaender, Malte Kriegs, Friederike Braig |
| Rok vydání: |
2023 |
| Popis: |
Head and neck squamous cell carcinomas (HNSCC) exhibiting resistance to the EGFR-targeting drug cetuximab poses a challenge to their effective clinical management. Here, we report a specific mechanism of resistance in this setting based upon the presence of a single nucleotide polymorphism encoding EGFR-K521 (K-allele), which is expressed in >40% of HNSCC cases. Patients expressing the K-allele showed significantly shorter progression-free survival upon palliative treatment with cetuximab plus chemotherapy or radiation. In several EGFR-mediated cancer models, cetuximab failed to inhibit downstream signaling or to kill cells harboring a high K-allele frequency. Cetuximab affinity for EGFR-K521 was reduced slightly, but ligand-mediated EGFR activation was intact. We found a lack of glycan sialyation on EGFR-K521 that associated with reduced protein stability, suggesting a structural basis for reduced cetuximab efficacy. CetuGEX, an antibody with optimized Fc glycosylation targeting the same epitope as cetuximab, restored HNSCC sensitivity in a manner associated with antibody-dependent cellular cytotoxicity rather than EGFR pathway inhibition. Overall, our results highlight EGFR-K521 expression as a key mechanism of cetuximab resistance to evaluate prospectively as a predictive biomarker in HNSCC patients. Further, they offer a preclinical rationale for the use of ADCC-optimized antibodies to treat tumors harboring this EGFR isoform. Cancer Res; 77(5); 1188–99. ©2016 AACR. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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