title: Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers.
abstract: Despite significant advances in early detection and treatment, breast cancer still remains a major cause of morbidity and mortality for women. Our understanding of the molecular heterogeneity of the disease has significantly expanded over the past decade and the role of cell cycle signaling in both breast cancer oncogenesis and anti-estrogen resistance has gained increasing attention. The mammalian cell cycle is driven by a complex interplay between cyclins and their associated cyclin-dependent kinase (CDK) partners, and dysregulation of this process is one of the hallmarks of cancer. Despite this, initial results with broadly acting CDK inhibitors were largely disappointing. However, recent preclinical and phase I/II clinical studies using a novel, oral, reversible CDK4/6 inhibitor, palbociclib (PD-0332991), have validated the role of CDK4/6 as a potential target in estrogen receptor-positive (ER+) breast cancers. This review highlights our current understanding of CDK signaling in both normal and malignant breast tissues, with special attention placed on recent clinical advances in inhibition of CDK4/6 in ER+ disease.
authors: Geffen School of Medicine at UCLA, Department of Medicine, Division of Hematology Oncology, 2825 Santa Monica Blvd, Santa Monica, CA, 90404, USA. rfinn@mednet.ucla.edu.
authors: Richard S
authors: RS
authors: Finn
authors: Geffen School of Medicine at UCLA, Department of Medicine, Division of Hematology Oncology, 2825 Santa Monica Blvd, Santa Monica, CA, 90404, USA.
authors: Alexey
authors: A
authors: Aleshin
authors: Stanford School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA.
authors: Dennis J
authors: DJ
authors: Slamon
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002986:Clinical Trials as Topic; D019938:Cyclin D1 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D006801:Humans; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib