title: Cyclin-dependent kinase pathways as targets for women's cancer treatment.
abstract: OBJECTIVE
  In this article, we not only review the preclinical and clinical studies of cyclin-dependent kinase (CDK) 4/6 inhibitors in breast cancer, liposarcoma, mantel cell lymphoma, melanoma and germ cell tumors, but also examine promising preclinical data in glioblastoma, renal and ovarian cancer models that may provide directions for future development.
  
  
  RESULTS
  Targeting CDKs has been the focus of considerable basic science and clinical research. The CDK 4/6 inhibitors are a novel class of therapeutics that target the CDK 4/6 kinases that promote transition through the cell cycle. Currently, palbociclib (PD0332991, Pfizer), abemaciclib (LY2835219, Lilly) and ribociclib (LEE011, Novartis) are being investigated in clinical trials. These oral agents offer the hope of clinical efficacy in many tumor types, and have been associated with minimal toxicity. Amplification/overexpression of cyclin D, loss of CDKN2A (p16) and amplification/overexpression of CDK4 are proposed biomarkers of improved response to CDK4/6 inhibition.
  
  
  CONCLUSIONS
  Palbociclib, abemaciclib and ribociclib have demonstrated very promising clinical activity in breast cancer, liposarcoma, mantel cell lymphoma and melanoma. Moreover, CDK4/6 inhibitors have shown promising preclinical activity in glioblastoma, renal and ovarian cancer models that may provide directions for their future clinical development. Further preclinical and clinical research is needed to better understand mechanisms of resistance and develop rational combination therapies with other targeted agents.
authors.affiliation: David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Gottfried E
authors.initials: GE
authors.lastname: Konecny
mesh_terms: D000631:Aminopyridines / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008080:Liposarcoma / Q000188:drug therapy*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D008545:Melanoma / Q000188:drug therapy*; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011725:Pyridines; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib; C000589651:ribociclib