Our results show that while upregulation of GRP78 by AA147 confers resistance to cisplatin, inhibition of GRP78 activity by YUM70 reduces HNSCC cell line viability, enhances cisplatin sensitivity, and induces cell death in cisplatin-resistant HNSCC cell lines both in 2D culture and in 3D spheroid models. This evidence concerns the gene HSPA5 and head and neck squamous cell carcinoma.