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Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K-521 Polymorphism

: Braig, F.; Kriegs, M.; Voigtlaender, M.; Habel, B.; Grob, T.; Biskup, K.; Blanchard, V.; Sack, M.; Thalhammer, A.; Ben Batalla, I.; Braren, I.; Laban, S.; Danielczyk, A.; Goletz, S.; Jakubowicz, E.; Märkl, B.; Trepel, M.; Knecht, R.; Riecken, K.; Fehse, B.; Loges, S.; Bokemeyer, C.; Binder, M.


Cancer research 77 (2017), No.5, pp.1188-1199
ISSN: 0008-5472
ISSN: 1538-7445
ISSN: 0099-7013
ISSN: 0099-7374
Deutsche Forschungsgemeinschaft DFG
BI 1711/1; B-Zell Rezeptor als Tumor Promotor bei der Chronischen Lymphatischen Leukämie und dem Mantelzell Lymphom
Journal Article
Fraunhofer IME ()

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.