CDK4: a master regulator of the cell cycle and its role in cancer

Abstract

The cell cycle is regulated in part by cyclins and their associated serine/threonine cyclin-dependent kinases, or CDKs. CDK4, in conjunction with the D-type cyclins, mediates progression through the G₁ phase when the cell prepares to initiate DNA synthesis. Although Cdk4-null mutant mice are viable and cell proliferation is not significantly affected in vitro due to compensatory roles played by other CDKs, this gene plays a key role in mammalian development and cancer. This review discusses the role that CDK4 plays in cell cycle control, normal development and tumorigenesis as well as the current status and utility of approved small molecule CDK4/6 inhibitors that are currently being used as cancer therapeutics.

Keywords: CDK4/6; cancer; cell cycle; checkpoint inhibitor; targeted therapy.

Figure 1. CDK4 regulation, activation and inhibition during cell cycle progression.

Structures of CDK4/6 specific small molecule inhibitors are shown on the right. (Adapted and modified from [50]).

Figure 2. Modulation of anti-tumor and immune responses by small molecule CDK4/6 and checkpoint inhibitors.

Figure 3. Mechanisms that underlie resistance to CDK4/6 inhibitors.

(Adapted and modified from [50]).