TY  - JOUR
A1  - Braig, Friederike
A1  - Kriegs, Malte
A1  - Voigtlaender, Minna
A1  - Habel, Beate
A1  - Grob, Tobias
A1  - Biskup, Karina
A1  - Blanchard, Veronique
A1  - Sack, Markus
A1  - Thalhammer, Anja
A1  - Ben Batalla, Isabel
A1  - Braren, Ingke
A1  - Laban, Simon
A1  - Danielczyk, Antje
A1  - Goletz, Steffen
A1  - Jakubowicz, Elzbieta
A1  - Maerkl, Bruno
A1  - Trepel, Martin
A1  - Knecht, Rainald
A1  - Riecken, Kristoffer
A1  - Fehse, Boris
A1  - Loges, Sonja
A1  - Bokemeyer, Carsten
A1  - Binder, Mascha
T1  - Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K-521 Polymorphism
JF  - Cancer research
N2  - 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-K-521 (K-allele), which is expressed in > 40% of HNSCC cases. Patients expressing the K-allele showed significantly shorter progressionfree 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-K-521 was reduced slightly, but ligand-mediated EGFR acti-vation was intact. We found a lack of glycan sialyation on EGFR-K-521 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-K-521 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.
Y1  - 2017
U6  - https://doi.org/10.1158/0008-5472.CAN-16-0754
SN  - 0008-5472
SN  - 1538-7445
VL  - 77
IS  - 5
SP  - 1188
EP  - 1199
PB  - American Association for Cancer Research
CY  - Philadelphia
ER  -