Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K521 Polymorphism

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-03, Vol.77 (5), p.1188-1199
• Main Authors: Braig, Friederike, Kriegs, Malte, Voigtlaender, Minna, Habel, Beate, Grob, Tobias, Biskup, Karina, Blanchard, Veronique, Sack, Markus, Thalhammer, Anja, Ben Batalla, Isabel, Braren, Ingke, Laban, Simon, Danielczyk, Antje, Goletz, Steffen, Jakubowicz, Elzbieta, Märkl, Bruno, Trepel, Martin, Knecht, Rainald, Riecken, Kristoffer, Fehse, Boris, Loges, Sonja, Bokemeyer, Carsten, Binder, Mascha
• Format: Article
• Language: English
• Subjects: Alleles; Cancer; Cancer therapies; Chemotherapy; Cytotoxicity; Epidermal growth factor receptors; Epitopes; Gene frequency; Gene polymorphism; Glycan; Glycosylation; Head & neck cancer; Head and neck carcinoma; Immunotherapy; Monoclonal antibodies; Radiation; Single-nucleotide polymorphism; Squamous cell carcinoma; Structural stability; Targeted cancer therapy; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-0754

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.