Short- and Long-Term Effects of CDK4/6 Inhibition on Early-Stage Breast Cancer

• Published in: Molecular cancer therapeutics Vol. 18; no. 12; pp. 2220 - 2232
• Main Authors: Kietzman, William B, Graham, Garrett T, Ory, Virginie, Sharif, Ghada M, Kushner, Max H, Gallanis, Gregory T, Kallakury, Bhaskar, Wellstein, Anton, Riegel, Anna T
• Format: Journal Article
• Language: English
• Published: United States 01.12.2019
• Subjects: Animals; Breast Neoplasms - drug therapy; Cell Proliferation; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - therapeutic use; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - therapeutic use; Female; Humans; Mice; Mice, Nude; Neoplasm Staging
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-19-0231

CDK4/6 inhibitors are used in the treatment of advanced estrogen receptor (ER)(+) breast cancer. Their efficacy in ER(-) and early-stage breast cancer is currently under investigation. Here, we show that palbociclib, a CDK4/6 inhibitor, can inhibit both progression of ductal carcinoma (DCIS) and growth of invasive disease in both an ER(-) basal breast cancer model (MCFDCIS) and an ER(+) luminal model (MCF7 intraductal injection). In MCFDCIS cells, palbociclib repressed cell-cycle gene expression, inhibited proliferation, induced senescence, and normalized tumorspheres formed in Matrigel while the formation of acini by normal mammary epithelial cells (MCF10A) was not affected. Palbociclib treatment of mice with MCFDCIS tumors inhibited their malignant progression and reduced proliferation of invasive lesions. Transcriptomic analysis of the tumor and stromal cell compartments showed that cell cycle and senescence genes, and , an ovarian cancer biomarker gene, were repressed during treatment. Knockdown of in MCFDCIS cells inhibited proliferation of invasive lesions but not progression of DCIS. After cessation of palbociclib treatment genes associated with differentiation, for example, , inflammation, IFNγ response, and antigen processing and presentation remained suppressed in the tumor and surrounding stroma. We conclude that palbociclib can prevent progression of DCIS and is antiproliferative in ER(-) invasive disease mediated in part via MUC16. Lasting effects of CDK4/6 inhibition after drug withdrawal on differentiation and the immune response could impact the approach to treatment of early-stage ER(-) breast cancer.