TY - JOUR
T1 - BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival
AU - Marchion, Douglas C.
AU - Cottrill, Hope M.
AU - Xiong, Yin
AU - Chen, Ning
AU - Bicaku, Elona
AU - Fulp, William J.
AU - Bansal, Nisha
AU - Chon, Hye Sook
AU - Stickles, Xiaomang B.
AU - Kamath, Siddharth G.
AU - Hakam, Ardeshir
AU - Li, Hua
AU - Su, Dan
AU - Moreno, Carolina
AU - Judson, Patricia L.
AU - Berchuck, Andrew
AU - Wenham, Robert M.
AU - Apte, Sachin M.
AU - Gonzalez-Bosquet, Jesus
AU - Bloom, Gregory C.
AU - Eschrich, Steven A.
AU - Sebti, Said
AU - Chen, Dung Tsa
AU - Lancaster, Johnathan M.
PY - 2011/10/1
Y1 - 2011/10/1
N2 - Purpose: 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. Experimental Design: 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 BADpathway 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). Conclusion: 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.
AB - Purpose: 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. Experimental Design: 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 BADpathway 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). Conclusion: 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.
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U2 - 10.1158/1078-0432.CCR-11-0735
DO - 10.1158/1078-0432.CCR-11-0735
M3 - Article
C2 - 21849418
AN - SCOPUS:80053483988
SN - 1078-0432
VL - 17
SP - 6356
EP - 6366
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -