title: Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer.
abstract: OBJECTIVE
  PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer.
  
  
  METHODS
  We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients.
  
  
  RESULTS
  Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time-dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95% CI 1.00-2.24, P = 0.052).
  
  
  CONCLUSIONS
  PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer.
authors.affiliation: Division of Hematology-Oncology, Department of Biomathematics and Biostatistics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. gkonecny@mednet.ucla.edu
authors.forename: Gottfried E
authors.initials: GE
authors.lastname: Konecny
authors.forename: Boris
authors.initials: B
authors.lastname: Winterhoff
authors.forename: Teodora
authors.initials: T
authors.lastname: Kolarova
authors.forename: Jingwei
authors.initials: J
authors.lastname: Qi
authors.forename: Kanthinh
authors.initials: K
authors.lastname: Manivong
authors.forename: Judy
authors.initials: J
authors.lastname: Dering
authors.forename: Guorong
authors.initials: G
authors.lastname: Yang
authors.forename: Meenal
authors.initials: M
authors.lastname: Chalukya
authors.forename: He-Jing
authors.initials: HJ
authors.lastname: Wang
authors.forename: Lee
authors.initials: L
authors.lastname: Anderson
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kalli
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.forename: Charles
authors.initials: C
authors.lastname: Ginther
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Darren
authors.initials: D
authors.lastname: Riehle
authors.forename: William A
authors.initials: WA
authors.lastname: Cliby
authors.forename: Sophia
authors.initials: S
authors.lastname: Randolph
authors.forename: Maria
authors.initials: M
authors.lastname: Koehler
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Hartmann
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015331:Cohort Studies; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D010879:Piperazines; D011725:Pyridines; D016160:Retinoblastoma Protein; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib