CDK4/CDK6 Inhibition and CDK4/CDK6 Inhibitors in Breast Cancer

Inhibition of CDK4/6 is a therapeutic strategy being investigated in patients with hormone receptor positive breast cancer in the adjuvant and neoadjuvant settings, as first-line therapy, and after resistance develops to endocrine therapy.

Cyclin D1 is a transcriptional target of the estrogen receptor and is involved in regulating entry into the synthesis phase (S phase) of the cell cycle. Cyclin D1 binds to cyclin dependent kinases 4 and 6 (CDK4/6), and this complex phosphorylates the retinoblastoma (RB1) tumor suppressor protein. The RB1 protein releases the transcription factors required for S phase entry in the cell cycle. CDK4/6 inhibitors block CDK4/6 from activating RB1 to promote the cell growth cycle.

Combining ER-targeting agents such as letrozole with agents that target downstream components of the ER pathway including CDK4/6 inhibitors is a vertical targeting strategy, and improves benefit cooperatively over standard of care single-agent therapy alone in clinical studies (Finn et al. 2015; Patnaik et al. 2014a, 2014b).

Several cell cycle inhibitors have been developed which target CDK4/6. Palbociclib is a kinase inhibitor targeting CDK4/6 that is FDA approved as a combination therapy with letrozole for the treatment of postmenopausal women with HER2-negative, hormone receptor positive breast cancer (FDA 2015; Finn et al. 2015). Ribociclib (LEE011) and abemaciclib (LY2835219) are two other kinase inhibitors targeting CDK4/6.

CDK4/6 Inhibitors in Breast Cancer

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2015. CDK4/6 Inhibition and CDK4/6 Inhibitors in Breast Cancer. My Cancer Genome http://www.padiracinnovation.org/content/molecular-medicine/cdk4cdk6-inhibition-and-cdk4cdk6-inhibitors-in-breast-cancer/ (Updated June 17).

Last Updated: June 24, 2015

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