title: PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially   inhibits proliferation of luminal estrogen receptor-positive human   breast cancer cell lines in vitro.
abstract: BACKGROUND
  Alterations in cell cycle regulators have been implicated in human malignancies including breast cancer. PD 0332991 is an orally active, highly selective inhibitor of the cyclin D kinases (CDK)4 and CDK6 with ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. To identify predictors of response, we determined the in vitro sensitivity to PD 0332991 across a panel of molecularly characterized human breast cancer cell lines.
  
  
  METHODS
  Forty-seven human breast cancer and immortalized cell lines representing the known molecular subgroups of breast cancer were treated with PD 0332991 to determine IC50 values. These data were analyzed against baseline gene expression data to identify genes associated with PD 0332991 response.
  
  
  RESULTS
  Cell lines representing luminal estrogen receptor-positive (ER+) subtype (including those that are HER2 amplified) were most sensitive to growth inhibition by PD 0332991 while nonluminal/basal subtypes were most resistant. Analysis of variance identified 450 differentially expressed genes between sensitive and resistant cells. pRb and cyclin D1 were elevated and CDKN2A (p16) was decreased in the most sensitive lines. Cell cycle analysis showed G0/G1 arrest in sensitive cell lines and Western blot analysis demonstrated that Rb phosphorylation is blocked in sensitive lines but not resistant lines. PD 0332991 was synergistic with tamoxifen and trastuzumab in ER+ and HER2-amplified cell lines, respectively. PD 0332991 enhanced sensitivity to tamoxifen in cell lines with conditioned resistance to ER blockade.
  
  
  CONCLUSIONS
  These studies suggest a role for CDK4/6 inhibition in some breast cancers and identify criteria for patient selection in clinical studies of PD 0332991
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, 10833 Le Conte Ave, 11-934 Factor Bldg, Los Angeles, CA 90095, USA. rfinn@mednet.ucla.edu
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.forename: Judy
authors.initials: J
authors.lastname: Dering
authors.forename: Dylan
authors.initials: D
authors.lastname: Conklin
authors.forename: Ondrej
authors.initials: O
authors.lastname: Kalous
authors.forename: David J
authors.initials: DJ
authors.lastname: Cohen
authors.forename: Amrita J
authors.initials: AJ
authors.lastname: Desai
authors.forename: Charles
authors.initials: C
authors.lastname: Ginther
authors.forename: Mohammad
authors.initials: M
authors.lastname: Atefi
authors.forename: Isan
authors.initials: I
authors.lastname: Chen
authors.forename: Camilla
authors.initials: C
authors.lastname: Fowst
authors.forename: Gerret
authors.initials: G
authors.lastname: Los
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004357:Drug Synergism; D020869:Gene Expression Profiling; D006801:Humans; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D011960:Receptors, Estrogen / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000378:metabolism; D013629:Tamoxifen / Q000008:administration & dosage; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D010879:Piperazines; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D016160:Retinoblastoma Protein; D013629:Tamoxifen; D000068878:Trastuzumab; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C500026:palbociclib