The Ras signaling pathway mediates cetuximab resistance in nasopharyngeal carcinoma

This work aimed to investigate the role of the Ras signaling pathway in cetuximab resistance in human nasopharyngeal carcinoma (hNPC). An hNPC 5-8F cell line was induced by stepwise exposure to increasing doses of cetuximab. Western blot was conducted to detect protein levels. Our results are as follows: cetuximab-resistant hNPC 5-8F/Erbitux cell lines were successfully developed. After treatment with cetuximab for 3 and 5 d, the RI was 1.2 and 1.1, respectively. Compared with the 5-8F cells, the protein expression levels of H-ras, JNK/P-JNK, P-ERK1/2, p38/P-p38, P-AKT, NF-κB p65/P-NF-κB p65 and c-fos were significantly increased in the 5-8F/Erbitux cells (P = 0.000 for all); however, the protein expression levels of ERK1/2 and c-jun/P-c-jun were significantly decreased (P = 0.000 for all) and AKT protein expression showed no significant change (P = 0.176). After the 5-8F/Erbitux cells were transfected with H-ras shRNA, H-ras protein expression was significantly decreased (P = 0.000) and cetuximab sensitivity improved. In contrast, in the 5-8F/Erbitux + siH-ras cells, protein expression levels of P-ERK1/2, P-JNK, P-AKT and NF-κB p65/P-NF-κB p65 were significantly decreased (P = 0.000 for all). Additionally, protein expression levels of JNK, ERK1/2, p38/P-p38 and c-jun/P-c-jun were significantly increased (P = 0.000 for all), but protein expression levels of AKT and c-fos did not change significantly (P = 0.061 and P = 0.068, respectively). In conclusion, the activation of the H-ras/ERK1/2, H-ras/JNK and PI3K-AKT signaling pathways is closely associated with cetuximab resistance in 5-8F/Erbitux cells. NF-κB is activated in 5-8F/Erbitux cells without activation of c-jun.