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Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer

Department of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129 Trieste, Italy
Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK
Department of Orthopedics and Orthopedic Oncology, University of Padova, 35128 Padova, Italy
Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
Authors to whom correspondence should be addressed.
Cells 2019, 8(4), 321;
Received: 25 February 2019 / Revised: 2 April 2019 / Accepted: 3 April 2019 / Published: 6 April 2019
Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in recent decades, improving the life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the Cyclin dependent kinase inhibitors family INK4 that specifically inhibit CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years, the CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in other BC subtypes. In HER2-positive BC, a combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, the efficacy of CDK4/6 inhibitors has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions for ongoing clinical trials and predictive biomarkers will be further debated. View Full-Text
Keywords: cyclin-dependent kinases; cyclin-dependent kinase 4 and 6 inhibitors; targeted therapies; breast cancer cyclin-dependent kinases; cyclin-dependent kinase 4 and 6 inhibitors; targeted therapies; breast cancer
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Sobhani, N.; D’Angelo, A.; Pittacolo, M.; Roviello, G.; Miccoli, A.; Corona, S.P.; Bernocchi, O.; Generali, D.; Otto, T. Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer. Cells 2019, 8, 321.

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