Noncanonical Pathways of Proteasome Inhibition in HPV-Negative Head & Neck Cancer

Abstract

Carfilzomib, a second-generation proteasome inhibitor approved for the treatment of multiple myeloma, is a highly potent and selective inhibitor of the CT-L activity of the i20S proteasome. Several studies have shown that carfilzomib (CFZ) can bypass resistance to bortezomib; however, its impact on squamous cell carcinoma of the head and neck is not well understood. This study aimed to evaluate the anticancer potential of CFZ in head and neck cancer cells (HNSCC) by examining its effects on proliferation, apoptosis, and the underlying mechanisms in both HPV-positive and HPV-negative HNSCC. In Vitro validation of CFZ showed an IC50 that was more than fourfold lower in HPV-negative CAL-27 than other HNSCC cell lines. In addition, CFZ inhibited p-Akt and p-S6 and activated p21, which increased growth inhibition and apoptosis in CAL-27 cells. In mice bearing xenografted HPV-negative CAL-27 cells, we confirmed that CFZ reduced tumor growth. Collectively, the cytotoxic effects induced by CFZ involve cell growth inhibition and apoptosis via the PI3K/AKT/mTOR and p21 signaling pathways. This suggests that CFZ is a novel therapeutic agent that can overcome the existing cisplatin resistance used in the treatment of HPV-negative HNSCC.