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

• Published in: American journal of translational research Vol. 11; no. 4; pp. 2370 - 2381
• Main Authors: Yang, Hua, Mo, Chuzi, Xun, Yang, Liu, Leyna G, Li, Wenxing, Guan, Jieying, Liu, Jing, Wu, Jianquan, Yang, Anping, Zheng, Songguo, Liu, Dahai, Liu, Fang
• Format: Journal Article
• Language: English
• Published: United States e-Century Publishing Corporation 01.01.2019
• Subjects: Original; ERK1/2; cetuximab resistance; Akt; Oral squamous cell carcinoma; Met; HGF
• ISSN: 1943-8141; 1943-8141

To investigate the underlying molecular mechanisms contributing to oral squamous cell carcinoma (OSCC) cell resistance to the epidermal growth factor receptor (EGFR) inhibitor. OSCC cell lines HSC-2 and HSC-3 were assessed for drug treatment, cell viability, and gene expression and the online gene expression in OSCC tissues was analyzed for association with OSCC prognosis. 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. 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.