1. Academic Validation
  2. CDK7 inhibitor THZ1 inhibits MCL1 synthesis and drives cholangiocarcinoma apoptosis in combination with BCL2/BCL-XL inhibitor ABT-263

CDK7 inhibitor THZ1 inhibits MCL1 synthesis and drives cholangiocarcinoma apoptosis in combination with BCL2/BCL-XL inhibitor ABT-263

  • Cell Death Dis. 2019 Aug 9;10(8):602. doi: 10.1038/s41419-019-1831-7.
Tianlu Huang 1 Xiwei Ding 1 Guifang Xu 1 Gang Chen 2 Yu Cao 1 Chunyan Peng 1 Shanshan Shen 1 Ying Lv 1 Lei Wang 3 Xiaoping Zou 4
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China.
  • 2 Division of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
  • 3 Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China. 867152094@qq.com.
  • 4 Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China. zouxp@nju.edu.cn.
Abstract

Cholangiocarcinoma (CCA) is a fatal disease without effective targeted therapy. We screened a small-molecule library of 116 inhibitors targeting different targets of the cell cycle and discovered several kinases, including Cyclin-dependent kinase 7 (CDK7) as vulnerabilities in CCA. Analysis of multiple CCA data sets demonstrated that CDK7 was overexpressed in CCA tissues. Further studies demonstrated that CDK7 Inhibitor THZ1 inhibited cell viability and induced Apoptosis in CCA cells. We also showed that THZ1 inhibited CCA cell growth in a xenograft model. RNA-sequencing followed by Gene ontology analysis showed a striking impact of THZ1 on DNA-templated transcriptional programs. THZ1 downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition. A number of oncogenic transcription factors and survival proteins, like MCL1, FOSL1, and RUNX1, were repressed by THZ1. MCL1, one of the antiapoptotic BCL2 family members, was significantly inhibited upon THZ1 treatment. Accordingly, combining THZ1 with a BCL2/Bcl-xL Inhibitor ABT-263 synergized in impairing cell growth and driving Apoptosis. Our results demonstrate CDK7 as a potential target in treating CCA. Combinations of CDK7 inhibition and BCL2/Bcl-xL inhibition may offer a novel therapeutic strategy for CCA.

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