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Cyclin‐Dependent Kinase Inhibitors for the Treatment of Breast Cancer: Past, Present, and Future
Author(s) -
DiPippo Adam J.,
Patel Neelam K.,
Barnett Chad M.
Publication year - 2016
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1002/phar.1756
Subject(s) - cyclin dependent kinase , fulvestrant , palbociclib , letrozole , metastatic breast cancer , cyclin dependent kinase 4 , pharmacology , cyclin dependent kinase 6 , cancer research , medicine , breast cancer , cdk inhibitor , restriction point , oncology , cell cycle , cancer , estrogen receptor , cyclin dependent kinase 2 , aromatase
Treatment of metastatic breast cancer ( MBC ) that is resistant to endocrine therapy presents a significant clinical challenge. The well‐known role of cell cycle dysregulation in these patients is partly mediated by cyclin‐dependent kinase ( CDK ) activity. Specific cyclin and CDK complexes regulate cell cycle progression by managing the transition through the cell cycle, and inhibition of CDK s represents an important target for novel agents. First‐generation CDK inhibitors (e.g., flavopiridol) were relatively nonselective and had an unacceptable toxicity profile in early trials. Second‐generation CDK inhibitors were designed to target the CDK 4 and CDK 6 ( CDK 4/6) pathway and have shown promising clinical activity with an acceptable toxicity profile in patients with MBC . Palbociclib is a first‐in‐class CDK 4/6 inhibitor that was granted accelerated U.S. Food and Drug Administration approval in combination with letrozole for the treatment of MBC in the first‐line setting (February 2015) as well as in combination with fulvestrant for MBC that had progressed on previous endocrine therapy (February 2016). Other CDK 4/6 inhibitors, including ribociclib and abemaciclib, are under investigation as monotherapy and in combination with endocrine or anti–human epidermal growth receptor 2 therapy for the treatment of MBC . Ongoing clinical trials should provide additional information to guide the appropriate use of these agents and identify patient populations that could derive the most benefit.