CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma
Cerise Yuen-Ki Chan1,2, David Kung-Chun Chiu1, Vincent Wai-Hin Yuen1,2
1Department of Pathology, The University of Hong Kong, Pok Fu Lam, Hong Kong Island, Hong Kong.
Abstract:
Deregulation of cell cycle is a typical feature of cancer cells. Normal cells rely on the strictly coordinated spindle assembly checkpoint (SAC) to maintain the genome integrity and survive. However, cancer cells could bypass this checkpoint mechanism. In this study, we showed the clinical relevance of threonine tyrosine kinase (TTK) protein kinase, a central regulator of the SAC, in hepatocellular carcinoma (HCC) and its potential as therapeutic target. Here, we reported that a newly developed, orally active small molecule inhibitor targeting TTK (CFI-402257) effectively suppressed HCC growth and induced highly aneuploid HCC cells, DNA damage, and micronuclei formation. We identified that CFI-402257 also induced cytosolic DNA, senescence-like response, and activated DDX41-STING cytosolic DNA sensing pathway to produce senescence-associated secretory phenotypes (SASPs) in HCC cells. These SASPs subsequently led to recruitment of different subsets of immune cells (natural killer cells, CD4+ T cells, and CD8+ T cells) for tumor clearance. Our mass cytometry data illustrated the dynamic changes in the tumor-infiltrating immune populations after treatment with CFI-402257. Further, CFI-402257 improved survival in HCC-bearing mice treated with anti-PD-1, suggesting the possibility of combination treatment with immune checkpoint inhibitors in HCC patients. In summary, our study characterized CFI-402257 as a potential therapeutic for HCC, both used as a single agent and in combination therapy.
Insights
A new TTK inhibitor, CFI-402257, shows promise for hepatocellular carcinoma (HCC) treatment. It triggers immune responses and enhances survival, suggesting potential as a single agent or in combination therapies.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Cancer cells often exhibit cell cycle deregulation, bypassing normal checkpoints like the spindle assembly checkpoint (SAC).
- Threonine tyrosine kinase (TTK) protein kinase is a key regulator of the SAC, and its role in hepatocellular carcinoma (HCC) warrants investigation.
- Targeting TTK presents a potential therapeutic strategy for HCC.
Purpose of the Study:
- To investigate the clinical relevance of TTK in HCC.
- To evaluate the therapeutic potential of a novel TTK inhibitor, CFI-402257, in HCC.
- To elucidate the mechanisms by which CFI-402257 exerts its anti-cancer effects.
Main Methods:
- Administration of CFI-402257, an orally active small molecule inhibitor of TTK.
- Assessment of HCC cell growth, aneuploidy, DNA damage, and micronuclei formation.
- Analysis of cytosolic DNA sensing pathways (DDX41-STING), senescence, and senescence-associated secretory phenotypes (SASPs).
- Mass cytometry to analyze tumor-infiltrating immune cells.
- Evaluation of CFI-402257 efficacy in HCC-bearing mice, including combination with anti-PD-1 therapy.
Main Results:
- CFI-402257 suppressed HCC growth and induced aneuploidy, DNA damage, and micronuclei formation.
- The inhibitor activated the DDX41-STING pathway, leading to SASP production and immune cell recruitment (NK, CD4+, CD8+ T cells).
- CFI-402257 demonstrated improved survival in mice, particularly when combined with anti-PD-1 therapy.
Conclusions:
- CFI-402257 is a promising therapeutic agent for HCC, acting as a single agent or in combination with immune checkpoint inhibitors.
- The drug's mechanism involves inducing immunogenic cell death through the activation of cytosolic DNA sensing pathways and SASP.
- This study highlights TTK as a viable therapeutic target and CFI-402257 as a potential treatment for HCC patients.
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