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

Abstract

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.

• Authors: Friederike Braig, Malte Kriegs, Minna Voigtlaender, Beate Habel, Tobias Grob, Karina Biskup, Veronique Blanchard, Markus Sack, Anja Thalhammer, Isabel Ben Batalla, Ingke Braren, Simon Laban, Antje Danielczyk, Steffen Goletz, Elzbieta Jakubowicz, Bruno Märkl, Martin Trepel, Rainald Knecht, Kristoffer Riecken, Boris Fehse, Sonja Loges, Carsten Bokemeyer, Mascha Binder
• Journal: Cancer research (Cancer Res) Vol. 77 Issue 5 Pg. 1188-1199 (03 01 2017) ISSN: 1538-7445 [Electronic] United States
• PMID: 28031227 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• EGFR protein, human
• ErbB Receptors
• Cetuximab

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Squamous Cell (drug therapy, enzymology, genetics)
• Cell Line, Tumor
• Cetuximab (pharmacology)
• Drug Resistance, Neoplasm
• ErbB Receptors (genetics)
• Female
• Head and Neck Neoplasms (drug therapy, enzymology, genetics)
• Humans
• Mice
• Mice, Inbred NOD
• Polymorphism, Single Nucleotide
• Random Allocation
• Signal Transduction
• Squamous Cell Carcinoma of Head and Neck
• Xenograft Model Antitumor Assays