Cyclin-Dependent Kinase 4 (CDK4) is an enzyme, specifically a serine/threonine kinase, that plays a regulatory role in cellular processes. As a member of the cyclin-dependent kinase family, it helps control cell growth and division. Cells undergo a tightly regulated series of events known as the cell cycle to ensure proper replication and division. CDK4’s function as a kinase means it can add phosphate groups to other proteins, an action that changes their activity and helps orchestrate the orderly progression of the cell cycle.
CDK4’s Role in Cell Cycle Control
CDK4 plays a role in regulating the cell cycle, particularly the transition from the G1 phase to the S phase. The G1 phase is a period of cell growth and preparation for DNA replication, which occurs in the S phase. This transition is controlled by a checkpoint that ensures the cell is ready to proceed to DNA synthesis without errors.
For CDK4 to become active, it must associate with Cyclin D. This partnership forms the Cyclin D/CDK4 complex, which acts as a molecular switch for cell division. Once activated, this complex targets the Retinoblastoma (Rb) protein.
The Cyclin D/CDK4 complex phosphorylates the Rb protein. In its unphosphorylated state, Rb binds to and inhibits transcription factors, such as E2F, which are responsible for activating genes needed for DNA replication. The phosphorylation of Rb by CDK4 causes it to release these E2F transcription factors. This release allows E2F to activate genes that promote the cell’s progression into the S phase, where DNA replication begins.
CDK4’s Link to Cancer
Dysregulation of CDK4 activity can contribute to uncontrolled cell proliferation. An overactive CDK4 can lead to continuous phosphorylation of the Rb protein, which keeps the cell cycle progression signals “on” without proper checks. This sustained activation allows cells to divide excessively, leading to tumor formation.
The mechanisms of CDK4 dysregulation in cancer are varied. One common way is the overexpression or amplification of the CDK4 gene itself. This has been observed in various cancers, including sarcomas, gliomas, lymphomas, and breast cancers. For example, CDK4 amplification is found in approximately 15.8% of breast carcinomas and is associated with higher tumor cell proliferation.
Alterations in CDK4’s partners, such as Cyclin D, or its inhibitors can lead to dysregulation. Overexpression of Cyclin D, which activates CDK4, is found in about 50% of human mammary carcinomas. Mutations in the CDK4 gene, such as the CDK4R24C mutation, can make it insensitive to natural inhibitory proteins, further promoting uncontrolled cell division. Such mutations were first identified in patients with familial melanoma. CDK4 overexpression has also been noted as a potential indicator for resistance to conventional chemotherapy in osteosarcoma patients.
Targeting CDK4 in Cancer Treatment
Understanding CDK4’s role in uncontrolled cell division has paved the way for targeted cancer therapies. CDK4/6 inhibitors are a class of drugs that block the activity of both CDK4 and CDK6. These inhibitors work by preventing the phosphorylation of the Rb protein, thereby keeping the cell in the G1 phase and inhibiting tumor growth.
Examples of these targeted drugs include palbociclib, ribociclib, and abemaciclib. Palbociclib was the first CDK4/6 inhibitor to demonstrate clinical effectiveness, followed by ribociclib and abemaciclib. These orally available drugs have different pharmacokinetic properties and dosing schedules; for instance, palbociclib and ribociclib are often administered on a three-weeks-on, one-week-off schedule to manage side effects like myelotoxicity, while abemaciclib is dosed continuously.
These inhibitors have shown success, particularly in treating hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. When combined with endocrine therapies like aromatase inhibitors or fulvestrant, they have demonstrated improved progression-free survival and overall survival in clinical trials such as MONALEESA-2, PALOMA-2, and MONARCH 3. This targeted approach offers a precise way to interfere with cancer cell growth, representing an advance over traditional, less specific chemotherapies.