From the Guidelines
CDK4/6 refers to cyclin-dependent kinases 4 and 6, which are enzymes that play a crucial role in regulating cell division and growth, and their inhibition has become a standard treatment for hormone receptor-positive, HER2-negative advanced breast cancer, as evidenced by the improved progression-free survival (PFS) and overall survival (OS) seen in several trials 1.
Definition and Function of CDK4/6
CDK4/6 are enzymes that control the transition from the G1 phase to the S phase in the cell cycle by partnering with D-type cyclins and phosphorylating the retinoblastoma protein (Rb). When CDK4/6 is activated, it helps release transcription factors that drive cell proliferation.
Role in Cancer
In cancer, particularly breast cancer, these enzymes are often overactive, leading to uncontrolled cell division. This discovery led to the development of CDK4/6 inhibitors like palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio), which work by blocking the activity of CDK4/6, thereby preventing cancer cells from dividing and slowing tumor growth.
Clinical Application
The use of CDK4/6 inhibitors in combination with endocrine therapy (ET) is now the standard-of-care for ER-positive, HER2-negative metastatic breast cancer (MBC), with improved PFS and OS and a good toxicity profile seen in several trials 1.
- CDK4/6 inhibitors are effective in de novo or recurrent MBC, in cases of primary or secondary endocrine resistance, in postmenopausal or premenopausal women, and in men.
- The efficacy of the three approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) appears similar, although they have slightly different toxicity profiles 1.
- ET alone in the first-line setting should be reserved for patients with comorbidities or a performance status that prevents the use of CDK4/6 inhibitor combinations.
From the FDA Drug Label
These kinases are activated upon binding to D-cyclins. Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and are downstream of signaling pathways which lead to cell cycle progression and cellular proliferation.
CDK4/6 (Cyclin-Dependent Kinases 4 and 6) are kinases that are activated upon binding to D-cyclins and play a role in cell cycle progression and cellular proliferation. They regulate cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). [2] [3]
From the Research
Definition and Function of CDK4/6
- CDK4 and CDK6 are downstream agents in the estrogen signaling pathway that control entry into the cell cycle 4
- They are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies 5
- CDK4/6 inhibition may prevent tumor cell progression in the cell cycle 4
Role in Cancer
- Constitutive activation of cyclin D–CDK4/6 represents the driving force of tumorigenesis in several cancer types 6
- CDK4/6 inhibitors have shown significant activity against several solid tumours, including breast cancer 7, 5
- They are rapidly transforming the care of patients with hormone receptor–positive, human epidermal growth factor receptor 2-negative advanced breast cancer 8
Mechanism of Action
- CDK4/6 inhibitors trigger cell cycle arrest in Rb protein (pRb)-competent cells 7
- They inhibit the phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells 5
- CDK4/6 inhibitors also promote anti-tumour immunity by activating tumour cell expression of endogenous retroviral elements and suppressing the proliferation of regulatory T cells 5
Clinical Use
- CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, are used in combination with endocrine therapy for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer 4, 7
- They have demonstrated significant clinical activity in combination with aromatase inhibitors or fulvestrant in women with HR+/HER2- advanced or metastatic breast cancer 4