Abstract B55: High expression of CDK6 protects breast cancer cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant treatment in estrogen receptor-positive metastatic breast cancer

Abstract

Abstract Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a major clinical problem. Recently, the CDK4/6 inhibitor palbociclib combined with letrozole was approved for treatment of ER+ advanced breast cancer, and other CDK4/6 inhibitors are also being investigated in clinical trials in combination with different endocrine treatments, including fulvestrant. However, the role of CDK4/6 in endocrine resistance and their potential as predictive biomarkers of endocrine treatment response remains to be defined. We evaluated the expression of genes of the cyclin D/CDK4-6/p16INK4A/Rb pathway in a panel of endocrine-resistant breast cancer cell lines by gene array and found increased expression of CDK6 in two fulvestrant-resistant cell models vs. sensitive cells. Reduction of CDK6 expression by specific gene knockdown impaired fulvestrant-resistant cells growth and induced apoptosis by reducing p70 ribosomal S6 kinase 2 activity. Treatment with palbociclib re-sensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma phosphorylation. Evaluation of CDK6 expression levels in metastatic samples from breast cancer patients treated with fulvestrant (N = 45) showed that high levels of CDK6 correlated significantly with shorter progression-free survival (PFS) (p = 0.0006), while no association was observed between CDK6 levels and PFS in patients receiving other endocrine treatments (N = 41, p = 0.874). Our results indicate that upregulation of CDK6 may be an important mechanism in overcoming fulvestrant-mediated growth inhibition in breast cancer cells. Patients with advanced ER+ breast cancer exhibiting high CDK6 expression in the metastatic lesions show shorter PFS upon fulvestrant treatment and thus may benefit from the addition of CDK4/6 inhibitors in their therapeutic regimens. Citation Format: Carla L. Alves, Daniel Elias, Maria Lyng, Martin Bak, Anne Lykkesfeldt, Henrik J. Ditzel. High expression of CDK6 protects breast cancer cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant treatment in estrogen receptor-positive metastatic breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B55.