title: PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity.
abstract: BACKGROUND
  PD-0332991 is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, and was evaluated to determine its anti-proliferative effects in 25 renal cell carcinoma (RCC) cell lines.
  
  
  METHODS
  Half-maximal inhibitory concentrations (IC50) of PD-0332991 were determined with cell line proliferation assays, as were its effects on the cell cycle, apoptosis, and retinoblastoma (RB) phosphorylation. Molecular markers for response prediction, including p16, p15, cyclin D1 (CCND1), cyclin E1 (CCNE1), E2F transcription factor 1 (E2F1), RB, CDK4 and CDK6, were studied using array comparative genomic hybridization (CGH) and gene expression.
  
  
  RESULTS
  IC50 values for PD-0332991 ranged from 25.0 nM to 700 nM, and the agent demonstrated G0/G1 cell-cycle arrest, induction of late apoptosis, and blockade of RB phosphorylation. Through genotype and expression data p16, p15 and E2F1 were identified as having significant association between loss and sensitivity to PD-0332991: p16 (p=0.021), p15 (p=0.047), and E2F1 (p=0.041).
  
  
  CONCLUSIONS
  PD-0332991 has antiproliferative activity in RCC cell lines, and molecular markers predict for sensitivity to this agent.
authors.affiliation: Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, 924 Westwood Blvd., Suite 1050, Los Angeles, CA 90095, USA. Joshuaelogan@gmail.com
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Logan
authors.forename: Nikayeh
authors.initials: N
authors.lastname: Mostofizadeh
authors.forename: Amrita J
authors.initials: AJ
authors.lastname: Desai
authors.forename: Erika
authors.initials: E
authors.lastname: VON Euw
authors.forename: Dylan
authors.initials: D
authors.lastname: Conklin
authors.forename: Veerauo
authors.initials: V
authors.lastname: Konkankit
authors.forename: Habib
authors.initials: H
authors.lastname: Hamidi
authors.forename: Mark
authors.initials: M
authors.lastname: Eckardt
authors.forename: Lee
authors.initials: L
authors.lastname: Anderson
authors.forename: Hsiao-Wang
authors.initials: HW
authors.lastname: Chen
authors.forename: Charles
authors.initials: C
authors.lastname: Ginther
authors.forename: Eileen
authors.initials: E
authors.lastname: Taschereau
authors.forename: Peter H
authors.initials: PH
authors.lastname: Bui
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Arie S
authors.initials: AS
authors.lastname: Belldegrun
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
authors.forename: Fairooz F
authors.initials: FF
authors.lastname: Kabbinavar
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D016160:Retinoblastoma Protein; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib
keywords: CDKN2A; E2F1; PD-0322991; Renal cell carcinoma; cell-cycle inhibition; p16; palbociclib