Combination of cetuximab with met inhibitor in control of cetuximab-resistant oral squamous cell carcinoma.

Abstract

<i>Objective:</i> To investigate the underlying molecular mechanisms contributing to oral squamous cell carcinoma (OSCC) cell resistance to the epidermal growth factor receptor (EGFR) inhibitor. <i>Materials and methods:</i> OSCC cell lines HSC-2 and HSC-3 were assessed <i>in vitro</i> for drug treatment, cell viability, and gene expression and the online gene expression in OSCC tissues was analyzed for association with OSCC prognosis. <i>Results:</i> HSC-2 and HSC-3 cells expressed high EGFR levels, but hepatocyte growth factor (HGF) treatment induced cetuximab resistance, whereas the Met inhibitor PHA-665752 as well as Met siRNA was able to restore OSCC cell sensitivity to cetuximab. HGF treatment induced tumor cells to express p-Akt and p-ERK1/2. In contrast, the activity of Akt and ERK1/2 was suppressed by treatment with PHA-665752, Met siRNA, or their combination. Furthermore, Met was highly expressed in OSCC tissues and associated with a poor patient survival, while Met/HGF-activated Akt also was associated with a poor patient survival. <i>Conclusions:</i> This study demonstrates that Met/HGF expression results in OSCC resistance to cetuximab and tumor recurrence after cetuximab therapy; thus, inhibition of Met/HGF activity could restore OSCC sensitivity to cetuximab.