BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival

Douglas C. Marchion, Hope M. Cottrill, Yin Xiong, Ning Chen, Elona Bicaku, William J. Fulp, Nisha Bansal, Hye Sook Chon, Xiaomang B. Stickles, Siddharth G. Kamath, Ardeshir Hakam, Hua Li, Dan Su, Carolina Moreno, Patricia L. Judson, Andrew Berchuck, Robert M. Wenham, Sachin M. Apte, Jesus Gonzalez-Bosquet, Gregory C. BloomSteven A. Eschrich, Said Sebti, Dung Tsa Chen, Johnathan M. Lancaster

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6356-6366
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number19
DOIs
StatePublished - Oct 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Marchion, D. C., Cottrill, H. M., Xiong, Y., Chen, N., Bicaku, E., Fulp, W. J., Bansal, N., Chon, H. S., Stickles, X. B., Kamath, S. G., Hakam, A., Li, H., Su, D., Moreno, C., Judson, P. L., Berchuck, A., Wenham, R. M., Apte, S. M., Gonzalez-Bosquet, J., ... Lancaster, J. M. (2011). BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival. Clinical Cancer Research, 17(19), 6356-6366. https://doi.org/10.1158/1078-0432.CCR-11-0735