Epithelial-mesenchymal transition markers and HER3 expression are predictors of elisidepsin treatment response in breast and pancreatic cancer cell lines

• Published in: PloS one 2013-01, Vol.8 (1), p.e53645-e53645
• Main Authors: Teixidó, Cristina, Marés, Rosó, Aracil, Miguel, Ramón y Cajal, Santiago, Hernández-Losa, Javier
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - therapeutic use; Biology; Biomarkers, Tumor - physiology; Biotechnology; Breast; Breast cancer; Breast carcinoma; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Cell Line, Tumor; Correlation; Cytotoxicity; Depsipeptides - therapeutic use; Development and progression; Drug dosages; Drug Resistance, Neoplasm; Epidermal growth factor; Epithelial-Mesenchymal Transition - physiology; Female; Gene expression; Humans; Kinases; Markers; MCF-7 Cells; Medicine; Mesenchyme; Pancreas; Pancreatic cancer; Pancreatic carcinoma; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pathology; Prostate cancer; Receptor, ErbB-3 - antagonists & inhibitors; Receptor, ErbB-3 - biosynthesis; Receptor, ErbB-3 - genetics; Receptors; Ribonucleic acid; RNA; Sensitivity; Stem cells; Tumor cell lines; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0053645

Elisidepsin (elisidepsin trifluoroacetate, Irvalec®, PM02734) is a new synthetic depsipeptide, a result of the PharmaMar Development Program that seeks synthetic products of marine origin-derived compounds. Elisidepsin is a drug with antiproliferative activity in a wide range of tumors. In the present work we studied and characterized the mechanisms associated with sensitivity and resistance to elisidepsin treatment in a broad panel of tumor cell lines from breast and pancreas carcinomas, focusing on different factors involved in epithelial-mesenchymal transition (EMT) and the use of HER family receptors in predicting the in vitro drug response. Interestingly, we observed that the basal protein expression levels of EMT markers show a significant correlation with cell viability in response to elisidepsin treatment in a panel of 12 different breast and pancreatic cancer cell lines. In addition, we generated three elisidepsin treatment-resistant cell lines (MCF-7, HPAC and AsPC-1) and analyzed the pattern of expression of different EMT markers in these cells, confirming that acquired resistance to elisidepsin is associated with a switch to the EMT state. Furthermore, a direct correlation between basal HER3 expression and sensitivity to elisidepsin was observed; moreover, modulation of HER3 expression levels in different cancer cell lines alter their sensitivities to the drug, making them more resistant when HER3 expression is downregulated by a HER3-specific short hairpin RNA and more sensitive when the receptor is overexpressed. These results show that HER3 expression is an important marker of sensitivity to elisidepsin treatment.