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

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Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-KPolymorphism. / 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.

In: CANCER RES, Vol. 77, No. 5, 01.03.2017, p. 1188-1199.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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 2017, 'Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-KPolymorphism', CANCER RES, vol. 77, no. 5, pp. 1188-1199. https://doi.org/10.1158/0008-5472.CAN-16-0754

APA

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., ... Binder, M. (2017). Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-KPolymorphism. CANCER RES, 77(5), 1188-1199. https://doi.org/10.1158/0008-5472.CAN-16-0754

Vancouver

Braig F, Kriegs M, Voigtlaender M, Habel B, Grob T, Biskup K et al. Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-KPolymorphism. CANCER RES. 2017 Mar 1;77(5):1188-1199. https://doi.org/10.1158/0008-5472.CAN-16-0754

Bibtex

@article{7c326fc02bc6411b930245e293f2c8f7,
title = "Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-KPolymorphism",
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. {\textcopyright}2016 AACR.",
keywords = "Animals, Antineoplastic Agents, Carcinoma, Squamous Cell, Cell Line, Tumor, Cetuximab, Drug Resistance, Neoplasm, Female, Head and Neck Neoplasms, Humans, Mice, Mice, Inbred NOD, Polymorphism, Single Nucleotide, Random Allocation, Receptor, Epidermal Growth Factor, Signal Transduction, Xenograft Model Antitumor Assays, Journal Article",
author = "Friederike Braig and Malte Kriegs and Minna Voigtlaender and Beate Habel and Tobias Grob and Karina Biskup and Veronique Blanchard and Markus Sack and Anja Thalhammer and {Ben Batalla}, Isabel and Ingke Braren and Simon Laban and Antje Danielczyk and Steffen Goletz and Elzbieta Jakubowicz and Bruno M{\"a}rkl and Martin Trepel and Rainald Knecht and Kristoffer Riecken and Boris Fehse and Sonja Loges and Carsten Bokemeyer and Mascha Binder",
note = "{\textcopyright}2016 American Association for Cancer Research.",
year = "2017",
month = mar,
day = "1",
doi = "10.1158/0008-5472.CAN-16-0754",
language = "English",
volume = "77",
pages = "1188--1199",
journal = "CANCER RES",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

RIS

TY - JOUR

T1 - Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-KPolymorphism

AU - Braig, Friederike

AU - Kriegs, Malte

AU - Voigtlaender, Minna

AU - Habel, Beate

AU - Grob, Tobias

AU - Biskup, Karina

AU - Blanchard, Veronique

AU - Sack, Markus

AU - Thalhammer, Anja

AU - Ben Batalla, Isabel

AU - Braren, Ingke

AU - Laban, Simon

AU - Danielczyk, Antje

AU - Goletz, Steffen

AU - Jakubowicz, Elzbieta

AU - Märkl, Bruno

AU - Trepel, Martin

AU - Knecht, Rainald

AU - Riecken, Kristoffer

AU - Fehse, Boris

AU - Loges, Sonja

AU - Bokemeyer, Carsten

AU - Binder, Mascha

N1 - ©2016 American Association for Cancer Research.

PY - 2017/3/1

Y1 - 2017/3/1

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-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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents

KW - Carcinoma, Squamous Cell

KW - Cell Line, Tumor

KW - Cetuximab

KW - Drug Resistance, Neoplasm

KW - Female

KW - Head and Neck Neoplasms

KW - Humans

KW - Mice

KW - Mice, Inbred NOD

KW - Polymorphism, Single Nucleotide

KW - Random Allocation

KW - Receptor, Epidermal Growth Factor

KW - Signal Transduction

KW - Xenograft Model Antitumor Assays

KW - Journal Article

U2 - 10.1158/0008-5472.CAN-16-0754

DO - 10.1158/0008-5472.CAN-16-0754

M3 - SCORING: Journal article

C2 - 28031227

VL - 77

SP - 1188

EP - 1199

JO - CANCER RES

JF - CANCER RES

SN - 0008-5472

IS - 5

ER -