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.
Highlights
Cholangiocarcinoma (CCA) is a malignancy with an upward trend in the incidence and mortality all over the world
Since the role of pololike kinase 1 (PLK1) has been studied in CCA before[24], we focused on the detailed study exploring the expression and function of Cyclindependent kinase 7 (CDK7) in CCA and examined the possibility of targeting CDK7 for the treatment of CCA
Since our findings suggested that CDK7 inhibition may synergize with ABT-263 through downregulation of MCL1 expression, we examined the function of MCL1 in the synergistic effect between THZ1 and ABT263 in CCA cells
Summary
Cholangiocarcinoma (CCA) is a malignancy with an upward trend in the incidence and mortality all over the world. CCA shows poor response to CCA is a complex disease and the pathogenesis is still unclear. In 2016, Yang et al identified 48 differentially expressed transcription factors in CCA compared with normal tissues by conducting integrated analysis of multiple CCA microarray data[2]. They found that the cell cycle was the most significant enriched pathway in CCA.
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