CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma

Deregulation of the cell cycle is a hallmark of cancer cells. Normal cells depend on the tightly regulated spindle assembly checkpoint (SAC) to maintain genomic integrity and ensure survival. In contrast, cancer cells often bypass this checkpoint. In this study, we explored the clinical significance of threonine tyrosine kinase (TTK), a key regulator of the SAC, in hepatocellular carcinoma (HCC), and its potential as a therapeutic target. We report that a newly developed orally active small molecule inhibitor, CFI-402257, effectively suppressed HCC growth, leading to highly aneuploid cells, DNA damage, and the formation of micronuclei. Additionally, CFI-402257 induced cytosolic DNA and a senescence-like response, activating the DDX41-STING cytosolic DNA sensing pathway, which produced senescence-associated secretory phenotypes (SASPs) in HCC cells. These SASPs subsequently recruited various immune cell subsets, including natural killer cells and CD4+ and CD8+ T cells, to aid in tumor clearance. Our mass cytometry data revealed dynamic changes in tumor-infiltrating immune populations following CFI-402257 treatment. Furthermore, CFI-402257 improved survival in HCC-bearing mice when combined with anti-PD-1 therapy, indicating the potential for combination treatments with immune checkpoint inhibitors in HCC patients. In summary, our study positions CFI-402257 as a promising therapeutic option for HCC, both as a standalone treatment and in combination therapies.