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.
Highlights
Head and neck squamous cell carcinomas (HNSCC) are among the most common types of newly diagnosed cancers in men with disappointing outcomes despite intensive treatment [1,2,3,4,5,6,7,8]
EGFRK521 status correlates with shorter progression-free survival in HNSCC patients undergoing cetuximab-based treatment
In line with this assumption, we found preserved cell attachment of cetuximab to EGFRK521, with slightly reduced affinity compared with EGFR
Summary
Head and neck squamous cell carcinomas (HNSCC) are among the most common types of newly diagnosed cancers in men with disappointing outcomes despite intensive treatment [1,2,3,4,5,6,7,8]. A mAb targeting the extracellular ligand-binding domain of the EGFR, has been shown to prolong overall survival in patients with recurrent or metastatic disease by about three months compared with chemotherapy alone It has been approved in combination with platinum-based chemotherapy There is, a clear need to understand the molecular mechanisms driving cetuximab resistance to maximize the likelihood of response by biomarkerdriven patient selection and to establish new treatment options to overcome resistance. In this context, a number of potential resistance-mediating molecular alterations and pathways have been studied in HNSCC. Whereas activating mutations of the Rat sarcoma genes (KRAS and NRAS) downstream of the GFR constitute an important mechanism of primary
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