Epidermal growth factor receptor (EGFR) is a key molecule in the pathophysiology of oesophageal
squamous cell carcinoma (OSCC). However, EGFR-targeted agents such as anti-EGFR antibody or
tyrosine kinase inhibitors for OSCC have not demonstrated any clinical benefits. Recently, a novel
chemotherapeutic agent, EGFR(2R)-lytic hybrid peptide, a composite of EGFR-binding peptide and lytic
peptide fragments, has been shown to exhibit a potent anti-tumour effect against cancers that express
high EGFR levels. In this study, we investigated the validity of employing EGFR(2R)-lytic hybrid peptide
against OSCC cells both in vitro and in vivo. Additionally, the toxicity of this peptide was assessed in
mice. We found high EGFR expression levels on the cell surface of OSCC cells, and the EGFR-binding
peptide fragment showed high affinity for OSCC cells. A potent cytotoxic effect was induced within
30 minutes by the exposure of OSCC cells to EGFR(2R)-lytic hybrid peptide. Furthermore, EGFR(2R)-lytic
hybrid peptide markedly suppressed the tumour growth of OSCC cells in a xenograft model. Moreover,
it did not cause any identifiable adverse effects in mice. Taken together, EGFR(2R)-lytic hybrid peptide
was shown to be a valid therapeutic agent against OSCC, providing a crucial rationale regarding novel
EGFR-targeted therapies against OSCC.