EGFR R521K Polymorphism Is Not a Major Determinant of Clinical Cetuximab Resistance in Head and Neck Cancer

SIMPLE SUMMARY: Malignant Head and neck squamous cell carcinomas occur frequently, and several treatment regimens are used to fight disease progression. While anti-Epidermal growth factor receptor (EGFR) antibody cetuximab is applied successfully in many cases, therapy resistance occurs after a short period in numerous patients. We checked the hypothesis whether EGFRvIII or EGFR R521K variants can be responsible for antibody efficacy or therapy resistance. EGFRvIII, unlike stated before, was found extremely rarely (<1%), while EGFR R521K was present in over 40% of the patients and suggested to be important in the preclinical models, but not in the clinical cohort. Conclusively, our results suggest that neither EGFRvIII nor EGFR R521K variants are directly resulting cetuximab resistance in Head and neck squamous cell carcinoma patients. ABSTRACT: Background: Head and neck squamous cell carcinomas (HNSCCs) are among the most abundant malignancies worldwide. Patients with recurrent/metastatic disease undergo combination chemotherapy containing cetuximab, the monoclonal antibody used against the epidermal growth factor receptor (EGFR). Cetuximab augments the effect of chemotherapy; however, a significant number of patients show therapy resistance. The mechanism of resistance is yet to be unveiled, although extracellular alterations of the receptor have been reported, and their role in cetuximab failure has been proposed. Aims: Here, we investigate possible effects of the multi-exon deletion variant (EGFRvIII), and the single nucleotide polymorphism EGFR R521K on cetuximab efficacy. Results: Our results show that in HNSCC patients, the EGFRvIII allele frequency is under 1%; therefore, it cannot lead to common resistance. EGFR R521K, present in 42% of the patients, is investigated in vitro in four HNSCC cell lines (two wild-type and two heterozygous for EGFR R521K). While no direct effect is found to be related to the EGFR status, cells harboring R521K show a reduced sensitivity in ADCC experiments and in vivo xenograft experiments. However, this preclinical difference is not reflected in the progression-free or overall survival of HNSCC patients. Furthermore, NK cell and macrophage presence in tumors is not related to EGFR R521K. Discussion: Our results suggest that EGFR R521K, unlike reported previously, is unable to cause cetuximab resistance in HNSCC patients; therefore, its screening before therapy selection is not justifiable