Therapeutic Targeting of MYC in Head and Neck Squamous Cell Carcinoma

Abstract

MYC plays critical roles in tumorigenesis and is considered an attractive cancer therapeutic target. Small molecules that directly target MYC and are well tolerated in vivo represent invaluable anti-cancer therapeutic agents. Here, we aimed to investigate the therapeutic effect of MYC inhibitors in head and neck squamous cell carcinoma (HNSCC). The results showed that pharmacological and genetic inhibition of MYC inhibited HNSCC proliferation and migration. MYC inhibitor 975 (MYCi975), inhibited HNSCC growth in both cell line-derived xenograft and syngeneic murine models. MYC inhibition also induced tumor cell-intrinsic immune responses, and promoted CD8+ T cell infiltration. Mechanistically, MYC inhibition increased CD8+ T cell-recruiting chemokines by inducing the DNA damage related cGAS-STING pathway. High expression of MYC combined with a low level of infiltrated CD8+ T cell in HNSCC correlated with poor prognosis. These results suggested the potential of small-molecule MYC inhibitors as anti-cancer therapeutic agents in HNSCC.

Keywords

• MYC
• head and neck squamous cell carcinoma
• MYCi975
• DNA damage response
• cGAS-STING
• CD8+ T cell