Converged DNA Damage Response Renders Human Hepatocellular Carcinoma Sensitive to CDK7 Inhibition

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC has a dismal five-year mortality estimate of >95%, ranking as the fourth leading cause of cancer-related mortality worldwide. Despite the recent progression in the treatment of HCC with multikinase inhibitors, immunotherapy, and antiangiogenic monoclonal antibodies, among other newly emerging therapeutics, the efficacy has varied among patients, making HCC a high priority for developing novel targeted therapeutic agents. CDK7 has been exploited as a therapeutic target in HCC. In the present study, we demonstrated that HCC cells were highly susceptible to THZ1, a selective covalent CDK7 inhibitor. We further discovered that transcription factor MYC-promoted cell proliferation renders cancer cells hypersensitive to apoptotic cell death with THZ1 treatment. Our findings indicate that targeting CDK7 with THZ1 may be a new plausible strategy for treating HCC, in which MYC plays crucial roles in cell proliferation and tumor growth. ABSTRACT: Hepatocellular carcinoma (HCC) is a lethal malignancy with high mortality. The inhibition of cyclin-dependent kinase 7 (CDK7) activity has shown therapeutic efficacy in HCC. However, the underlying molecular mechanisms remain elusive. Here, we show that three HCC lines, HepG2, Hep3B, and SK-Hep-1, were highly susceptible to the CDK7 inhibitor THZ1. In mouse models, THZ1 effectively reduced HepG2 tumor growth and tumor weight. THZ1 arrested cell cycle and triggered MYC-related apoptosis in HepG2. To evaluate how MYC protein levels affected THZ1-induced apoptotic cell death, we overexpressed MYC in HepG2 and found that exogenously overexpressed MYC promoted cell cycle progression and increased cells in the S phase. THZ1 drastically engendered the apoptosis of MYC-overexpressing HepG2 cells in the S and G2/M phases. Importantly, transcription-inhibition-induced apoptosis is associated with DNA damage, and exogenous MYC expression further enhanced the THZ1-induced DNA damage response in MYC-overexpressing HepG2 cells. Consistently, in the HepG2 xenografts, THZ1 treatment was associated with DNA-damage-induced cell death. Together, our data indicate that the converged effect of MYC-promoted cell cycle progression and CDK7 inhibition by THZ1 confers the hypersensitivity of HCC to DNA-damage-induced cell death. Our findings may suggest a new therapeutic strategy of THZ1 against HCC.