학술논문
CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma.
Document Type
Article
Author
Yuen-Ki Chan, Cerise; Kung-Chun Chiu, David; Wai-Hin Yuen, Vincent; Cheuk-Ting Law; Bowie Po-Yee Wong; Lynn Thu, Kelsie; Cescon, David Ward; Soria-Bretones, Isabel; Wing-Sum Cheu, Jacinth; Lee, Derek; Aki Pui-Wah Tse; Shuo Zhang, Misty; Kel Vin Tan; Oi-Lin Ng, Irene; Pek-Lan Khong; Chung-Cheung Yau, Thomas; Bray, Mark Robert; Tak Wah Mak; Chak-Lui Wong, Carmen
Source
Subject
*HEMOPHILIACS
*HEPATOCELLULAR carcinoma
*KILLER cells
*SMALL molecules
*IMMUNE checkpoint inhibitors
*PROTEIN-tyrosine kinases
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Language
ISSN
0027-8424
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. [ABSTRACT FROM AUTHOR]