Cyclin-dependent kinase (CDK) 4/6 inhibitors are novel agents that have shown promising results in the treatment of breast cancer. CDK4 and CDK6 are proteins that are part of a cell cycle regulatory pathway that also includes p16, cyclin D, and the retinoblastoma (Rb) protein. CDK4/6 inhibitors bind to CDK4 and CDK6, preventing phosphorylation of the Rb protein. This halts cell cycle progression and induces G1 cell cycle arrest. Malignant cells frequently acquire mutations in the CDK4/6 pathway, either activating mutations of CDK4/6 or mutations in CDK4/6 regulatory mechanisms, thereby conferring a growth advantage. By inhibiting CDK4/6, tumor cells are unable to exploit this pathway for cell proliferation.
In vitro studies show robust activity of CDK4/6 inhibitors in multiple types of cancer, including breast cancer. Estrogen receptor (ER)-positive luminal breast cancer cell lines were shown to be particularly sensitive to CDK4/6 inhibition. Early clinical studies have demonstrated improvement in progression-free survival with use of these agents in patients with ER-positive breast cancer. With the success of CDK4/6 inhibitors in early clinical trials, several phase 3 trials evaluating these agents in breast cancer1 are now under way, and they may soon become an important component of combination cancer therapy.
One of the most promising novel therapies for breast cancer involves interrupting cell cycle progression through cyclin-dependent kinase (CDK) inhibition. Several agents acting on this pathway are in early- and late-phase trials. This review describes the biologic pathways involved in this therapy, reviews the status of current agents and trials, and looks at future directions for this class of drugs.
Mechanism of Action—CDK 4/6 Pathway
Normal cell cycle progression is tightly regulated by several mechanisms that control cell growth and division. Alterations in these mechanisms contribute to malignant transformation of cells and uncontrolled cell proliferation. Cyclin-dependent kinases play a key role in the progression of the cell cycle from the first growth phase (G1) through the DNA synthesis (S) phase, the second growth phase (G2), and ultimately, mitosis, or (M) phase.1
Recently developed targeted therapies take aim at cell cycle pathways, such as the CDK4/6 pathway (Figure
). Proteins in this cell proliferative pathway include p16, an endogenous suppressor of CDK4/6, cyclin D1, the regulatory subunit of CDK4/6, and retinoblastoma (Rb) protein, a tumor suppressor.
Cyclin D1 was the first described G1 phase cyclin.2
Approximately 15% of human breast cancers demonstrate amplification of the cyclin D1 gene, CCND1
, and the majority of human breast cancers show overexpression of this protein.3,4
Cyclin D1 is a key component of cell cycle progression and interacts closely with the Rb protein. In the hypo-phosphorylated state, Rb protein acts as a tumor suppressor and contributes to cell cycle regulation at the G1 to S checkpoint by suppressing gene transcription that is required for entry into the S phase. The cell cycle is then arrested in G1. In response to mitogenic signals, CDK4 and CDK6 form a complex with their regulatory subunit, cyclin D1, which phosphorylates the Rb protein, reducing its ability to suppress gene transcription. Controlled phosphorylation and deactivation of the Rb protein by the CDK4/6 complex is essential to progression of the normal cell cycle.5
In malignant cells, unrestricted CDK4/6 pathway activity can result from alterations in the expression of cyclin-dependent kinases and their regulatory mechanisms. This unhindered cell cycle stimulation yields a growth advantage and uncontrolled cell proliferation.6
Figure 1. CDK4/6 Cell Cycle Pathway
Recognition of CDK4/6 pathway proteins as novel targets in anti-cancer therapy led to the development of pan-CDK inhibitors which non-selectively inhibit the cell cycle and affect normal cells, leading to high rates of adverse events (AEs) and excessive toxicity.7-9
With selective CDK4/6 inhibition, normal cells can utilize other cyclin-dependent kinases, such as CDK2, to proceed with normal cell growth.1