In vitro analysis of ovarian cancer response to cisplatin, carboplatin, and paclitaxel identifies common pathways that are also associated with overall patient survival

• Published in: British journal of cancer Vol. 106; no. 12; pp. 1967 - 1975
• Main Authors: Bicaku, E, Xiong, Y, Marchion, D C, Chon, H S, Stickles, X B, Chen, N, Judson, P L, Hakam, A, Gonzalez-Bosquet, J, Wenham, R M, Apte, S M, Fulp, W, Cubitt, C L, Chen, D-T, Lancaster, J M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.06.2012; Nature Publishing Group
• Subjects: 631/67/1059/602; 631/80/86; 692/699/67/1517/1709; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carboplatin - administration & dosage; Cell Line, Tumor - immunology; Cisplatin - administration & dosage; Cyclic AMP Response Element-Binding Protein; Drug Resistance; Epidemiology; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Molecular Medicine; Oncology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - mortality; Paclitaxel - administration & dosage; Signal Transduction; Translational Therapeutics; Treatment Outcome; Tumors; chemo-response; taxane; ovarian cancer; platinum agents; gene expression; Antineoplastic agent; Human; Ovary cancer; Malignant tumor; Gene expression; In vitro; Survival; Cisplatin; Female genital diseases; Ovarian diseases; Alkylating agent; Cancerology; Taxane derivatives; Paclitaxel; Carboplatin; Antimitotic; Cancer; Platinum II Complexes
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/bjc.2012.207

Background: Carboplatin and cisplatin, alone or in combination with paclitaxel, have similar efficacies against ovarian cancer (OVCA) yet exhibit different toxicity profiles. We characterised the common and unique cellular pathways that underlie OVCA response to these drugs and analyse whether they have a role in OVCA survival. Methods: Ovarian cancer cell lines ( n =36) were treated with carboplatin, cisplatin, paclitaxel, or carboplatin–paclitaxel (CPTX). For each cell line, IC 50 levels were quantified and pre-treatment gene expression analyses were performed. Genes demonstrating expression/IC 50 correlations (measured by Pearson; P <0.01) were subjected to biological pathway analysis. An independent OVCA clinico-genomic data set ( n =142) was evaluated for clinical features associated with represented pathways. Results: Cell line sensitivity to carboplatin, cisplatin, paclitaxel, and CPTX was associated with the expression of 77, 68, 64, and 25 biological pathways ( P <0.01), respectively. We found three common pathways when drug combinations were compared. Expression of one pathway (‘Transcription/CREB pathway’) was associated with OVCA overall survival. Conclusion: The identification of the Transcription/CREB pathway (associated with OVCA cell line platinum sensitivity and overall survival) could improve patient stratification for treatment with current therapies and the rational selection of future OVCA therapy agents targeted to these pathways.