Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer
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 differe...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-04-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/8/4/321 |
| _version_ | 1797723087604547584 |
|---|---|
| author | Navid Sobhani Alberto D’Angelo Matteo Pittacolo Giandomenico Roviello Anna Miccoli Silvia Paola Corona Ottavia Bernocchi Daniele Generali Tobias Otto |
| author_facet | Navid Sobhani Alberto D’Angelo Matteo Pittacolo Giandomenico Roviello Anna Miccoli Silvia Paola Corona Ottavia Bernocchi Daniele Generali Tobias Otto |
| author_sort | Navid Sobhani |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T09:58:00Z |
| format | Article |
| id | doaj.art-01cb87ee541546d1bd2b934be545326f |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T09:58:00Z |
| publishDate | 2019-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-01cb87ee541546d1bd2b934be545326f2023-09-02T12:00:11ZengMDPI AGCells2073-44092019-04-018432110.3390/cells8040321cells8040321Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast CancerNavid Sobhani0Alberto D’Angelo1Matteo Pittacolo2Giandomenico Roviello3Anna Miccoli4Silvia Paola Corona5Ottavia Bernocchi6Daniele Generali7Tobias Otto8Department of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129 Trieste, ItalyDepartment of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UKDepartment of Orthopedics and Orthopedic Oncology, University of Padova, 35128 Padova, ItalyDepartment of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129 Trieste, ItalyDepartment of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129 Trieste, ItalyDepartment of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129 Trieste, ItalyDepartment of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129 Trieste, ItalyDepartment of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129 Trieste, ItalyDepartment of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, GermanyBreast 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.https://www.mdpi.com/2073-4409/8/4/321cyclin-dependent kinasescyclin-dependent kinase 4 and 6 inhibitorstargeted therapiesbreast cancer |
| spellingShingle | Navid Sobhani Alberto D’Angelo Matteo Pittacolo Giandomenico Roviello Anna Miccoli Silvia Paola Corona Ottavia Bernocchi Daniele Generali Tobias Otto Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer Cells cyclin-dependent kinases cyclin-dependent kinase 4 and 6 inhibitors targeted therapies breast cancer |
| title | Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer |
| title_full | Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer |
| title_fullStr | Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer |
| title_full_unstemmed | Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer |
| title_short | Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer |
| title_sort | updates on the cdk4 6 inhibitory strategy and combinations in breast cancer |
| topic | cyclin-dependent kinases cyclin-dependent kinase 4 and 6 inhibitors targeted therapies breast cancer |
| url | https://www.mdpi.com/2073-4409/8/4/321 |
| work_keys_str_mv | AT navidsobhani updatesonthecdk46inhibitorystrategyandcombinationsinbreastcancer AT albertodangelo updatesonthecdk46inhibitorystrategyandcombinationsinbreastcancer AT matteopittacolo updatesonthecdk46inhibitorystrategyandcombinationsinbreastcancer AT giandomenicoroviello updatesonthecdk46inhibitorystrategyandcombinationsinbreastcancer AT annamiccoli updatesonthecdk46inhibitorystrategyandcombinationsinbreastcancer AT silviapaolacorona updatesonthecdk46inhibitorystrategyandcombinationsinbreastcancer AT ottaviabernocchi updatesonthecdk46inhibitorystrategyandcombinationsinbreastcancer AT danielegenerali updatesonthecdk46inhibitorystrategyandcombinationsinbreastcancer AT tobiasotto updatesonthecdk46inhibitorystrategyandcombinationsinbreastcancer |