Role of cyclin‐dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway

Abstract

Liver cancer is the fourth leading cause of cancer related mortality in the world, with hepatocellular carcinoma (HCC) representing the most common primary subtype. Two‐thirds of HCC patients have advanced disease when diagnosed, and for these patients, treatment strategies remain limited. In addition, there is a high incidence of tumor recurrence after surgical resection with the current treatment regimens. The development of novel and more effective agents is required. Cyclin‐dependent kinases (CDKs) constitute a family of 21 different protein kinases involved in regulating cell proliferation, apoptosis, and drug resistance, and are evaluated in preclinical and clinical trials as chemotherapeutics. To summarize and discuss the therapeutic potential of targeting CDKs in HCC, recent published articles identified from PubMed were comprehensively reviewed. The key words included hepatocellular carcinoma, cyclin‐dependent kinases, and CDK inhibitors. This review focuses on the emerging evidence from studies describing the genetic and functional aspects of CDKs in HCC. We also present an overview of CDK inhibitors that have shown efficacy in laboratory studies of HCC. Although many of the studies assessing CDK‐targeting therapies in HCC are at the preclinical stage, there is significant evidence that CDK inhibitors used alone or in combination with established chemotherapy drugs could have significant applications in HCC.

Kinome-centric pharmacoproteomics identifies signaling pathways underlying cellular responses to targeted cancer drugs

“…Mining of our dataset and additional functional studies revealed a FZD2-AXL-NUAK1/2 signaling module that is highly active in mesenchymal HCC cells. Remarkably, when we inhibited either NUAK1, NUAK2 or AXL by RNAi knockdown or pharmacological inhibition mesenchymal HCC cells underwent MET, in turn activating targets of clinical and preclinical HCC drugs such as the FGFR and the cell cycle (17,33). Confoundingly, this MET-dependent increase in cell cycle activity was accompanied by induction of DNA damage response signaling, indicating that rapidly dividing epithelial HCC cells suffer from near-catastrophic replication stress (44).…”

“…Therefore, in a clinical setting, these findings would suggest that patient 4 is most likely to respond to sorafenib or regorafenib treatment. In contrast, CDK inhibitor pathway markers were highly enriched in 3 out of 4 tumors (r ~0.4 to ~0.5, Figure 2C), indicating that most patients would respond to CDK inhibitor treatment, for instance with dinaciclib or flavopiridol, which are currently in clinical trials for HCC (33). Collectively, these data establish for the first time that kinome activity-based biomarkers can be detected in human tissue specimens, possibly paving the way for future clinical trials of personalized therapies based on such pathway-based biomarkers.…”

Previous and current knowledge on cell cycle‐related molecules in hepatocellular carcinoma: Potential therapeutic targets of cell cycle‐related molecules in hepatocellular carcinoma

“…The Cdk inhibitors used in current phase II clinical trials also comprise many Cdk molecules that inhibit the G1 to S phase transition. 1 Subsequently, this review article also reported that Cdk1 was overexpressed in liver cancer. 9 Blocking the G2 to M phase transition in cancer cells through the inhibition of Cdk1 has also been shown to suppress the growth of hepatocellular carcinoma cells in vitro and in vivo, which might be particularly effective against cancer cells resistant to conventional anticancer drugs.…”

“…The review article by Shen et al . contained intriguing information on cell cycle‐related molecules associated with recent investigations into cell proliferation, apoptosis, and drug resistance . Furthermore, their review suggested that cell cycle‐related molecule might be used as a molecular target for therapeutic agents against hepatocellular carcinoma in the near future.…”

“…In this review, the article by Shen et al ., mostly describes the involvement of Cdk4/6 in the G1 to S phase transition. The Cdk inhibitors used in current phase II clinical trials also comprise many Cdk molecules that inhibit the G1 to S phase transition …”