The application and prospect of CDK4/6 inhibitors in malignant solid tumors

Abstract

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, which block the transition from the G1 to S phase of the cell cycle by interfering with Rb phosphorylation and E2F release, have shown potent antitumor activity and manageable toxicity in HR+/HER2- breast cancer patients. Some clinical trials involving CDK4/6 inhibitors in other tumors have achieved preliminary impressive efficacy. Whether CDK4/6 inhibitors possess great potential as broad-spectrum antitumor drugs and how to maximize their clinical benefits remain uncertain. TCGA database analysis showed that CDK4/6 genes and related genes are widely expressed among various tumors, and high or moderate expression of CDK4/6 genes commonly indicates poor survival. CDK4/6 gene expression is significantly higher in COAD, ESCA, STAD, LIHC, and HNSC, suggesting that CDK4/6 inhibitors could be more efficacious in those tumors. Moreover, network analysis with the STRING database demonstrated that CDK4/6-related proteins were co-expressed or co-occurred with the classical tumor signaling pathways, such as the cell cycle pathway, RAS pathway, PI3K pathway, Myc pathway, and p53 pathway. The extensive antitumor effects of CDK4/6 inhibitors may be achieved by synergizing or antagonizing with other signaling molecule inhibitors, and combination therapy might be the most effective treatment strategy. This article analyzed the feasibility of expanding the application of CDK4/6 inhibitors at the genetic level and further summarized the associated clinical/preclinical studies to collect supportive evidence. This is the first study that presents a theoretical foundation for CDK4/6 inhibitor precision therapy via combined analysis of comprehensive gene information and clinical research results.

Keywords: CDK4/6 inhibitors; Cell cycle; Malignancy; TCGA database; Tumor signaling pathway.

Fig. 1

The role of CDK4/6 in the cell cycle

Fig. 2

CDK4/6-related gene information among various cancers. a Expression of CDK4/6 and related genes. b Comparison of the expression of CDK4/6-related genes between tumor and normal tissues. c Alteration frequency of CDK4/6-related genes

Fig. 3

Expression levels of CDK4/6-related genes and its corresponding survival

Fig. 4

Functional protein association networks of CDK4/6 and classical tumor signaling pathways