title: Treating cancer with selective CDK4/6 inhibitors.
abstract: 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.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: O'Leary
authors.affiliation: Division of Haematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.|Breast Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Turner
mesh_terms: D000631:Aminopyridines / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D002986:Clinical Trials as Topic; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D005260:Female; D005544:Forecasting; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use; D011687:Purines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use
chemical_list: D000631:Aminopyridines; D001562:Benzimidazoles; D010879:Piperazines; D011687:Purines; D011725:Pyridines; D019938:Cyclin D1; C000590451:abemaciclib; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib; C000589651:ribociclib