Taken together, our results suggest that the AKT/ERK-p53-bcl-2 axis might constitute a signaling cascade that mediates the antitumor treatment in HNSCC cells, and hTERT targeting could be an attractive approach in combination with conventional chemotherapies for patients suffering from chemo-insensitivity or refractory HNSCC. Here, BCL2 is linked to head and neck squamous cell carcinoma.