Ribociclib Mechanism of Action
Ribociclib (Kisqali) is a cyclin-dependent kinase (CDK) 4 and 6 inhibitor used in HR-positive, HER2-negative breast cancer in combination with endocrine therapy. [1] Ribociclib inhibits the CDK4/6 pathway that controls cell-cycle progression from G1 to S phase. [1]
Molecular Pathway Targeted
Ribociclib inhibits CDK4 and CDK6 activity. [1] Cyclin D–CDK4/6 regulates cell-cycle progression through phosphorylation of the retinoblastoma protein (pRb). [1] Ribociclib decreases pRb phosphorylation. [1] Reduced pRb phosphorylation leads to cell-cycle arrest in the G1 phase. [1]
Antitumor Effect in Breast Cancer Cells
Ribociclib reduced cell proliferation in breast cancer cell lines in vitro. [1] Ribociclib induced G1 phase cell-cycle arrest in pRb-positive breast cancer cells in preclinical testing. [2]
Use With Endocrine Therapy Context
Kisqali is indicated in combination with an aromatase inhibitor for HR-positive, HER2-negative advanced or metastatic breast cancer. [3] The drug is also used with endocrine therapy-based treatment strategies for this disease context. [1]
Key Practical Mechanistic Implications
Cell-cycle arrest is driven by inhibition of pRb phosphorylation within the CDK4/6 axis. [1] Activity is therefore mechanistically linked to the functionality of the pRb pathway. [2]
Safety-Relevant Mechanistic Association
Concentration-dependent QTc interval increases have been described in patients treated with Kisqali, including when combined with aromatase inhibitors. [1]