The roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer

Abstract

Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.