BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival.

Published

Journal Article

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.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.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).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.

Full Text

Duke Authors

Cited Authors

  • Marchion, DC; Cottrill, HM; Xiong, Y; Chen, N; Bicaku, E; Fulp, WJ; Bansal, N; Chon, HS; Stickles, XB; Kamath, SG; Hakam, A; Li, L; Su, D; Moreno, C; Judson, PL; Berchuck, A; Wenham, RM; Apte, SM; Gonzalez-Bosquet, J; Bloom, GC; Eschrich, SA; Sebti, S; Chen, D-T; Lancaster, JM

Published Date

  • October 2011

Published In

Volume / Issue

  • 17 / 19

Start / End Page

  • 6356 - 6366

PubMed ID

  • 21849418

Pubmed Central ID

  • 21849418

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-11-0735

Language

  • eng