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CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Aug 09; Vol. 119 (32), pp. e2119514119. Date of Electronic Publication: 2022 Aug 01. - Publication Year :
- 2022
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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 <superscript>+</superscript> T cells, and CD8 <superscript>+</superscript> 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.
- Subjects :
- Animals
CD4-Positive T-Lymphocytes metabolism
CD8-Positive T-Lymphocytes metabolism
Cell Cycle Proteins metabolism
Cell Line, Tumor
Cell Proliferation
Killer Cells, Natural metabolism
Mice
Protein Serine-Threonine Kinases
Protein-Tyrosine Kinases metabolism
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular genetics
Liver Neoplasms drug therapy
Liver Neoplasms genetics
Protein Kinase Inhibitors therapeutic use
Pyrazoles therapeutic use
Pyrimidines therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 119
- Issue :
- 32
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 35914158
- Full Text :
- https://doi.org/10.1073/pnas.2119514119