title: Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K521Polymorphism.
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-K521was reduced slightly, but ligand-mediated EGFR activation was intact. We found a lack of glycan sialyation on EGFR-K521that 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-K521expression 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.affiliation: Department of Oncology and Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Braig
authors.affiliation: Radiation Biology and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Kriegs
authors.affiliation: Department of Oncology and Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Minna
authors.initials: M
authors.lastname: Voigtlaender
authors.affiliation: Bioassays and Nonclinical Studies, GLYCOTOPE GmbH, Berlin, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Habel
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Grob
authors.affiliation: Institute for Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité University Medical Center Berlin, Berlin, Germany.
authors.forename: Karina
authors.initials: K
authors.lastname: Biskup
authors.affiliation: Institute for Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité University Medical Center Berlin, Berlin, Germany.
authors.forename: Veronique
authors.initials: V
authors.lastname: Blanchard
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Sack
authors.affiliation: Department of Physical Biochemistry, Potsdam University, Potsdam, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Thalhammer
authors.affiliation: Department of Oncology and Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ben Batalla
authors.affiliation: HEXT Vector Facility/Institute for Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ingke
authors.initials: I
authors.lastname: Braren
authors.affiliation: Department of Oto-Rhino-Laryngology and Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Laban
authors.affiliation: Bioassays and Nonclinical Studies, GLYCOTOPE GmbH, Berlin, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Danielczyk
authors.affiliation: Bioassays and Nonclinical Studies, GLYCOTOPE GmbH, Berlin, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Goletz
authors.affiliation: Pathological Institute, Klinikum Augsburg, Augsburg, Germany.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Jakubowicz
authors.affiliation: Pathological Institute, Klinikum Augsburg, Augsburg, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Märkl
authors.affiliation: Department of Oncology and Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Oncology and Hematology, Klinikum Augsburg, Augsburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Trepel
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Cancer Center of the University Cancer Center Hamburg, University Medical Center Hamburg, Hamburg, Germany.
authors.forename: Rainald
authors.initials: R
authors.lastname: Knecht
authors.affiliation: Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Riecken
authors.affiliation: Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Fehse
authors.affiliation: Department of Oncology and Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Loges
authors.affiliation: Department of Oncology and Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Department of Oncology and Hematology, BMT with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. m.binder@uke.de.
authors.forename: Mascha
authors.initials: M
authors.lastname: Binder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D020641:Polymorphism, Single Nucleotide; D011897:Random Allocation; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab