title: BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival.
abstract: OBJECTIVE
  Despite initial sensitivity to chemotherapy, ovarian cancers (OVCA) often develop drug resistance, which limits patient survival. Using specimens and/or genomic data from 289 patients and a panel of cancer cell lines, we explored genome-wide expression changes that underlie the evolution of OVCA chemoresistance and characterized the BCL2 antagonist of cell death (BAD) apoptosis pathway as a determinant of chemosensitivity and patient survival.
  
  
  METHODS
  Serial OVCA cell cisplatin treatments were performed in parallel with measurements of genome-wide expression changes. Pathway analysis was carried out on genes associated with increasing cisplatin resistance (EC(50)). BAD-pathway expression and BAD protein phosphorylation were evaluated in patient samples and cell lines as determinants of chemosensitivity and/or clinical outcome and as therapeutic targets.
  
  
  RESULTS
  Induced in vitro OVCA cisplatin resistance was associated with BAD-pathway expression (P < 0.001). In OVCA cell lines and primary specimens, BAD protein phosphorylation was associated with platinum resistance (n = 147, P < 0.0001) and also with overall patient survival (n = 134, P = 0.0007). Targeted modulation of BAD-phosphorylation levels influenced cisplatin sensitivity. A 47-gene BAD-pathway score was associated with in vitro phosphorylated BAD levels and with survival in 142 patients with advanced-stage (III/IV) serous OVCA. Integration of BAD-phosphorylation or BAD-pathway score with OVCA surgical cytoreductive status was significantly associated with overall survival by log-rank test (P = 0.004 and P < 0.0001, respectively).
  
  
  CONCLUSIONS
  The BAD apoptosis pathway influences OVCA chemosensitivity and overall survival, likely via modulation of BAD phosphorylation. The pathway has clinical relevance as a biomarker of therapeutic response, patient survival, and as a promising therapeutic target.
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33647, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Marchion
authors.forename: Hope M
authors.initials: HM
authors.lastname: Cottrill
authors.forename: Yin
authors.initials: Y
authors.lastname: Xiong
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Elona
authors.initials: E
authors.lastname: Bicaku
authors.forename: William J
authors.initials: WJ
authors.lastname: Fulp
authors.forename: Nisha
authors.initials: N
authors.lastname: Bansal
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Chon
authors.forename: Xiaomang B
authors.initials: XB
authors.lastname: Stickles
authors.forename: Siddharth G
authors.initials: SG
authors.lastname: Kamath
authors.forename: Ardeshir
authors.initials: A
authors.lastname: Hakam
authors.forename: Lihua
authors.initials: L
authors.lastname: Li
authors.forename: Dan
authors.initials: D
authors.lastname: Su
authors.forename: Carolina
authors.initials: C
authors.lastname: Moreno
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Judson
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.forename: Robert M
authors.initials: RM
authors.lastname: Wenham
authors.forename: Sachin M
authors.initials: SM
authors.lastname: Apte
authors.forename: Jesus
authors.initials: J
authors.lastname: Gonzalez-Bosquet
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Bloom
authors.forename: Steven A
authors.initials: SA
authors.lastname: Eschrich
authors.forename: Said
authors.initials: S
authors.lastname: Sebti
authors.forename: Dung-Tsa
authors.initials: DT
authors.lastname: Chen
authors.forename: Johnathan M
authors.initials: JM
authors.lastname: Lancaster
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D010766:Phosphorylation; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C494819:BAD protein, human; D051025:bcl-Associated Death Protein; D002945:Cisplatin