Therapeutic Targeting of CDK7 Suppresses Tumor Progression in Intrahepatic Cholangiocarcinoma.
Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy with high mortality and lack of effective therapeutic targets. Here, we found that expression of cyclin-dependent kinase 7 (CDK7) was significantly associated with higher tumor grade and worse prognosis in 96 ICC specimens. Depletion of CDK7 significantly inhibited cell growth, induced a G2/M cell cycle arrest, and reduced the migratory and invasive potential in ICC cells. Subsequent experiments demonstrated that ICC cells were highly sensitive to the CDK7 inhibitor THZ1. A low concentration of THZ1 markedly inhibited cell growth, cell cycle, migration, and invasion in ICC cell lines. RNA-sequencing (RNA-seq) analysis revealed that THZ1 treatment decreased the levels of massive oncogene transcripts, particularly those associated with cell cycle and cell migration. Quantitative reverse transcriptase PCR (qRT-PCR) analysis confirmed that transcription of oncogenes involved in cell cycle regulation (AURKA, AURKB, CDC25B, CDK1, CCNA2, and MKI67) and the c-Met pathway (c-Met, AKT1, PTK2, CRK, PDPK1, and ARF6) was selectively repressed by THZ1. In addition, THZ1 exhibited significant anti-tumor activity in a patient-derived xenograft (PDX) model of ICC, without causing detectable side effects.
['Chen|Hua-Dong|HD|', 'Huang|Chen-Song|CS|', 'Xu|Qiong-Cong|QC|', 'Li|Fuxi|F|', 'Huang|Xi-Tai|XT|', 'Wang|Jie-Qin|JQ|', 'Li|Shi-Jin|SJ|', 'Zhao|Wei|W|', 'Yin|Xiao-Yu|XY|']
D000818:Animals D002453:Cell Cycle D045744:Cell Line, Tumor D002465:Cell Movement D002470:Cell Survival D018281:Cholangiocarcinoma D018844:Cyclin-Dependent Kinases D005260:Female D006801:Humans D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D008875:Middle Aged D000081246:RNA-Seq D060888:Real-Time Polymerase Chain Reaction
Intrahepatic cholangiocarcinoma Cyclin-dependent Kinase 7 Cell cycle THZ1 c-Met