Cyclin-Dependent Kinase Inhibitors for the Treatment of Breast Cancer: Past, Present, and Future

被引:60
作者
DiPippo, Adam J. [1 ]
Patel, Neelam K. [1 ]
Barnett, Chad M. [1 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Div Pharm, 1515 Holcombe Blvd,Unit 90, Houston, TX 77030 USA
来源
PHARMACOTHERAPY | 2016年 / 36卷 / 06期
关键词
metastatic breast cancer; cyclin-dependent kinase inhibitors; palbociclib; ribociclib; abemaciclib; PHASE IB; LEE011;
D O I
10.1002/phar.1756
中图分类号
R9 [药学];
学科分类号
100702 [药剂学];
摘要
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 CDKs 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 CDK4 and CDK6 (CDK4/6) pathway and have shown promising clinical activity with an acceptable toxicity profile in patients with MBC. Palbociclib is a first-in-class CDK4/6 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 CDK4/6 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.
引用
收藏
页码:652 / 667
页数:16
相关论文
共 47 条
[1]
[Anonymous], ASCO M ABSTRACTS S
[2]
[Anonymous], 2015, SEER: cancer stat facts: female breast cancer
[3]
[Anonymous], J CLIN ONCOL OFF J S
[4]
The history and future of targeting cyclin-dependent kinases in cancer therapy [J].
Asghar, Uzma ;
Witkiewicz, Agnieszka K. ;
Turner, Nicholas C. ;
Knudsen, Erik S. .
NATURE REVIEWS DRUG DISCOVERY, 2015, 14 (02) :130-146
[5]
The emergence of targeted drugs in breast cancer to prevent resistance to endocrine treatment and chemotherapy [J].
Austreid, Eilin ;
Lonning, Per Eystein ;
Eikesdal, Hans Petter .
EXPERT OPINION ON PHARMACOTHERAPY, 2014, 15 (05) :681-700
[6]
Triple blockade with LEE011, everolimus, and exemestane in women with ER+/HER2-advanced/metastatic breast cancer: results from a Phase Ib clinical trial [J].
Bardia, A. ;
Chavez-MacGregor, C. ;
Modi, S. ;
Campone, M. ;
Ma, B. ;
Kittaneh, M. ;
Dirix, L. ;
Motta, M. ;
Zhang, V. ;
Bhansali, S. ;
Fjaellskog, M. L. ;
Oliveira, M. .
EUROPEAN JOURNAL OF CANCER, 2014, 50 :163-163
[7]
Bardia A, 2014, J CLIN ONCOL, V32
[8]
Beaver J, 2015, CLIN REV IBRANCE PAL
[9]
A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days [J].
Benson, C. ;
White, J. ;
De Bono, J. ;
O'Donnell, A. ;
Raynaud, F. ;
Cruickshank, C. ;
McGrath, H. ;
Walton, M. ;
Workman, P. ;
Kaye, S. ;
Cassidy, J. ;
Gianella-Borradori, A. ;
Judson, I. ;
Twelves, C. .
BRITISH JOURNAL OF CANCER, 2007, 96 (01) :29-37
[10]
Cyclin dependent kinases in cancer Potential for therapeutic intervention [J].
Canavese, Miriam ;
Santo, Loredana ;
Raje, Noopur .
CANCER BIOLOGY & THERAPY, 2012, 13 (07) :451-457