BAD Phosphorylation Determines Ovarian Cancer Chemosensitivity and Patient Survival

• Published in: Clinical cancer research Vol. 17; no. 19; pp. 6356 - 6366
• Main Authors: MARCHION, Douglas C, COTTRILL, Hope M, HAKAM, Ardeshir, LIHUA LI, DAN SU, MORENO, Carolina, JUDSON, Patricia L, BERCHUCK, Andrew, WENHAM, Robert M, ATE, Sachin M, GONZALEZ-BOSQUET, Jesus, BLOOM, Gregory C, YIN XIONG, ESCHRICH, Steven A, SEBTI, Said, CHEN, Dung-Tsa, LANCASTER, Johnathan M, NING CHEN, BICAKU, Elona, FULP, William J, BANSAL, Nisha, HYE SOOK CHON, STICKLES, Xiaomang B, KAMATH, Siddharth G
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.2011
• Subjects: Antineoplastic agents; Antineoplastic Agents - therapeutic use; bcl-Associated Death Protein - genetics; bcl-Associated Death Protein - metabolism; Biological and medical sciences; Cisplatin - therapeutic use; Drug Resistance, Neoplasm - genetics; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - mortality; Pharmacology. Drug treatments; Phosphorylation; Signal Transduction; Tumor Cells, Cultured; Tumors; Human; Ovarian diseases; Phosphorylation; Ovary cancer; Chemosensitivity; Patient; Malignant tumor; Survival; Cancer; Female genital diseases
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-0735

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.