CDK4 as a Prognostic Marker of Hepatocellular Carcinoma and CDK4 Inhibitors as Potential Therapeutics.

ABSTRACT

BACKGROUND: The proteins CDK4 and CDK6, which are extremely homologous, control cell cycle entry. For the treatment of breast tumors that include hormone receptors, CDK4 and CDK6 inhibitors have been authorized. The link between CDK4 and liver hepatocellular carcinoma (LIHC), however, has not yet been established. OBJECTIVE: The study aimed to explore the link between CDK4 and LIHC and the effect of CDK4 inhibitors on LIHC. METHOD: In this study, we have evaluated CDK4's prognostic relevance in LIHC using data from The Cancer Genome Atlas (TCGA). The relationship between clinical-pathologic features and CDK4 expression has been evaluated using the Kruskal-Wallis test, the Wilcoxon signed-rank test, and logistic regression. We have analyzed CDK4 and factors related to the prognosis of HCC using the Kaplan-Meier technique and multivariate Cox regression. Gene set enrichment analysis (GSEA) identified CDK4-related critical pathways. To investigate the connections between CDK4 and cancer immune infiltrates, TCGA data were employed in single-sample gene set enrichment analysis (ssGSEA). For functional validation, CDK4 was chosen since it can be inhibited by recognized CDK4/ 6-inhibitors (e.g., abemaciclib). RESULTS: Poorer overall and disease-specific outcomes were linked to high CDK4 expression in HCC patients. GSEA suggested that CDK4 and immune response are closely connected. The amount of Th2 cells infiltrating was positively correlated with CDK4 expression, while the amount of cytotoxic cells infiltrating was negatively correlated, according to ssGSEA. Both in vitro and in vivo, the anti-tumor efficacy of CDK4 inhibitor has been found to be superior to that of sorafenib. CONCLUSION: This study suggests a relationship between CDK4 and immune infiltration and prognosis in HCC. Additionally, a CDK4 inhibitor may have anti-tumor properties against hepatocellular cancer.