Therapeutic Targeting of CDK7 Suppresses Tumor Progression in Intrahepatic Cholangiocarcinoma

Abstract

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.

CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism

“…We further discovered that THZ1 treatment remarkably decreased anti-apoptotic protein BCL2 and increased cleaved caspase 3 in B-ALL cells, suggesting that the therapeutic effect of CDK7 inhibitor was dependent on triggering programmed cell death. Our findings are consistent with the results that are reported in solid tumors (8,9,11,13,14). We also confirmed that the inhibitory effect of THZ1 on B-ALL cells was associated with the reduction of CTD phosphorylation of RNA Pol II at Ser-2, Ser-5, and Ser-7.…”

“…Previous studies indicated that different THZ1 concentrations have distinct cytotoxic effects on tumor cells, with low THZ1 concentrations inhibiting cell proliferation and high THZ1 concentrations inducing cell apoptosis (13,14). Cell apoptosis was tested by Annexin-V and PI double staining to evaluate whether THZ1 could induce cell death of B-ALL cells in a high concentration.…”

“…Therefore, CDK7 is a potential drug target for the treatment of tumors. THZ1 is the first selective and covalent CDK7 inhibitor, which shows antitumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis (11)(12)(13)(14). However, whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains unclear.…”

Evolution of the Experimental Models of Cholangiocarcinoma

“…This prolonged time should be considered as a negative factor when PDX models would be used as "Avatars" for therapy personalization. [56] iCCA NSG FGFR2-CCDC6 gene fusion [215] iCCA NGS DH1 R132C mutation [216] iCCA NOD/SCID Constitutive expression of FGFR 1-4 mRNA and FRS2 [217] iCCA CD1 immunodeficient nude NOTCH1 overexpression [219] iCCA B-NDG miceBALB/c (nu/nu) nude CDK7 overexpression [220] iCCA NOD/SCID YAP overexpression [204] iCCA Balb/c RJ mice Oct-3/4 or Sox2 expression [60] iCCA NOD/SCID Sodium-dependent vitamin C transporter 2 (SVCT-2) expression [221] eCCA Balb/c RJ mice Oct-3/4 or Sox2 expression [60] iCCA: intrahepatic cholangiocarcinoma; eCCA: extrahepatic cholangiocarcinoma; NOD/SCID: nonobese diabetic/severe combined immunodeficiency; NSG: NOD-scid IL2rγ null ; B-NDG; NOD-Prkdc scid IL2rg tm1 /Bcgen.…”

Efficacy of the CDK7 Inhibitor on EMT-Associated Resistance to 3rd Generation EGFR-TKIs in Non-Small Cell Lung Cancer Cell Lines

“…We have previously observed that the mechanisms of the anticancer activity of CDK7 inhibitors were associated with cell cycle arrest and the apoptosis of various cancer cells [16,[32][33][34]. Thus, we analyzed the cell cycle and apoptosis.…”