title: CDK4/6 inhibitors in breast cancer.
abstract: Deregulation of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) axis can occur through a number of mechanisms and contributes towards the unrestrained growth witnessed in a variety of cancers including breast cancers. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising preclinical and clinical results in breast cancer and other tumours. A number of trials assessing antitumour efficacy in various disease settings and combinations are ongoing. The cyclin D1-CDK-Rb axis and its role in the cell cycle of normal and cancer cells are delineated. The early pan-CDK inhibitor flavopiridol and subsequent preclinical and clinical development of selective CDK4/6 inhibitors are described. Ongoing studies in breast cancer with novel CDK4/6 inhibitors (palbociclib, abemaciclib and ribociclib) are explored. A literature search of these topics was performed through PubMed. Abstracts from major oncology meetings were also reviewed. Selective CDK4/6 inhibitors, as represented by the competing compounds currently in clinical development, comprise a novel, safe and, thus far, promisingly efficacious group of drugs. Considerable resources are being devoted towards exploring the efficacy of these drugs in combination with endocrine therapies, an approach that has yielded encouraging results and accelerated approval by the US Food and Drugs Administration for one of these agents (palbociclib). The results of confirmatory phase 3 trials are, however, awaited. We discuss further therapy combinations in development and highlight potential areas for caution including the potential for antagonistic interactions with cytotoxic chemotherapies.
authors.affiliation: aDepartment of Medical Oncology, Bon Secours Hospital, Cork bSchool of Medicine, University College Cork, Ireland cSchool of Medicine, Deakin University, Geelong, Victoria dNHMRC CTC University of Sydney, New South Wales, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Dukelow
authors.forename: Divya
authors.initials: D
authors.lastname: Kishan
authors.forename: Mustafa
authors.initials: M
authors.lastname: Khasraw
authors.forename: Conleth G
authors.initials: CG
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002986:Clinical Trials as Topic; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6