Journal article
BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival
Clinical cancer research, Vol.17(19), pp.6356-6366
10/01/2011
DOI: 10.1158/1078-0432.CCR-11-0735
PMCID: PMC3186862
PMID: 21849418
Abstract
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.
Details
- Title: Subtitle
- BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival
- Creators
- Douglas C Marchion - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33647, USAHope M CottrillYin XiongNing ChenElona BicakuWilliam J FulpNisha BansalHye Sook ChonXiaomang B SticklesSiddharth G KamathArdeshir HakamLihua LiDan SuCarolina MorenoPatricia L JudsonAndrew BerchuckRobert M WenhamSachin M ApteJesus Gonzalez-BosquetGregory C BloomSteven A EschrichSaid SebtiDung-Tsa ChenJohnathan M Lancaster
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.17(19), pp.6356-6366
- Publisher
- United States
- DOI
- 10.1158/1078-0432.CCR-11-0735
- PMID
- 21849418
- PMCID
- PMC3186862
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Grant note
- R21 CA110499 / NCI NIH HHS R21 CA110499-01A2 / NCI NIH HHS R03 AG028100-02 / NIA NIH HHS R03 AG028100 / NIA NIH HHS R21 CA-110499-01A2 / NCI NIH HHS P30 CA076292 / NCI NIH HHS
- Language
- English
- Date published
- 10/01/2011
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9983930273202771
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