Treating cancer with selective CDK4/6 inhibitors.
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Date
2016-07-01Author
O'Leary, B
Finn, RS
Turner, NC
Type
Journal Article
Metadata
Show full item recordAbstract
Uncontrolled cellular proliferation, mediated by dysregulation of the cell-cycle machinery and activation of cyclin-dependent kinases (CDKs) to promote cell-cycle progression, lies at the heart of cancer as a pathological process. Clinical implementation of first-generation, nonselective CDK inhibitors, designed to inhibit this proliferation, was originally hampered by the high risk of toxicity and lack of efficacy noted with these agents. The emergence of a new generation of selective CDK4/6 inhibitors, including ribociclib, abemaciclib and palbociclib, has enabled tumour types in which CDK4/6 has a pivotal role in the G1-to-S-phase cell-cycle transition to be targeted with improved effectiveness, and fewer adverse effects. Results of pivotal phase III trials investigating palbociclib in patients with advanced-stage oestrogen receptor (ER)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a well-tolerated toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge that, although unwelcome, might enable rational post-CDK4/6 inhibitor therapeutic strategies to be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast cancer is challenging, and will likely require biomarkers that are predictive of a response, and the use of combination therapies in order to optimize CDK4/6 targeting.
Collections
Subject
Humans
Neoplasms
Breast Neoplasms
Aminopyridines
Piperazines
Pyridines
Benzimidazoles
Purines
Cyclin D1
Antineoplastic Combined Chemotherapy Protocols
Cell Cycle
Forecasting
Female
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Clinical Trials as Topic
Molecular Targeted Therapy
Research team
Molecular Oncology
Language
eng
License start date
2016-07
Citation
Nature reviews. Clinical oncology, 2016, 13 (7), pp. 417 - 430
Publisher
NATURE PUBLISHING GROUP