Abstract IA07: Targeting the cyclin D-CDK4/6 pathway for cancer therapy

Abstract

Abstract The cyclin D-CDK4/6 kinase complex plays a pivotal role in the stimulation of cellular proliferation through phosphorylation and functional inactivation of the retinoblastoma protein (pRb), which leads to commitment of G1-phase cells to enter S phase, and ultimately to complete the mitotic cell cycle. Cancer cells frequently escape normal constraints on cell proliferation via persistent inactivation of pRb, through dysregulation of cyclin D-CDK4/6 kinase activity or loss of pRb expression. Interestingly, estrogen-positive (ER+) breast cancer cells rarely show loss of pRb, and hence rely on inappropriate activation of cyclin D-CDK4/6 to drive malignant proliferation. ER+ breast cancer therefore represents an enriched patient population in which to test the efficacy of cyclin D-CDK4/6 inhibition as a therapeutic strategy. Palbociclib, a selective cyclin D-CDK4/6 inhibitor, was approved by the FDA in 2015 for the treatment of women with advanced ER+/HER2- breast cancer. The drug is administered in combination with an anti-hormonal agent, which underscores the critical, collaborative roles of dysregulated estrogen receptor and cyclin D-CDK4/6 activities in driving tumor growth in this breast cancer subtype. This presentation will review the cellular pharmacology of palbociclib, with a particular emphasis on the phenotypic outcomes of combined estrogen receptor and cyclin D-CDK4/6 inhibition in human breast cancer cell lines. In addition, we will provide an update on the clinical activities of palbociclib in breast cancer, as well as prospects for therapeutic targeting of cyclin D-CDK4/6 activity in other cancer subtypes. Citation Format: Robert T. Abraham. Targeting the cyclin D-CDK4/6 pathway for cancer therapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA07.