TY - JOUR T1 - A Gene Expression Signature Associated With Overall Survival in Patients With Hepatocellular Carcinoma Suggests a New Treatment Strategy JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.115.101360 SP - mol.115.101360 AU - Jean-Pierre Gillet AU - Jesper B. Andersen AU - James P. Madigan AU - Sudhir Varma AU - Rachel K. Bagni AU - Katie Powell AU - William E. Burgan AU - Chung-Pu Wu AU - Anna Maria Calcagno AU - Suresh V. Ambudkar AU - Snorri S. Thorgeirsson AU - Michael Gottesman Y1 - 2015/01/01 UR - http://molpharm.aspetjournals.org/content/early/2015/12/14/mol.115.101360.abstract N2 - Despite improvements in the management of liver cancer, the survival rate for individuals with hepatocellular carcinoma (HCC) remains dismal. The survival benefit of systemic chemotherapy for the treatment of liver cancer is only marginal. Although the reasons for treatment failure are multifactorial, intrinsic resistance to chemotherapy plays a primary role. Here, we analyzed the expression of 377 multidrug resistance-associated genes in two independent cohorts of patients with advanced hepatocellular carcinoma, with the aim of finding ways to improve survival in this poor-prognosis cancer. Taqman-based qPCR revealed a 45-gene signature that predicts overall survival (OS) in patients with HCC. Using the Connectivity Map Tool, we were able to identify drugs that converted the gene expression profiles of HCC cell lines from ones matching patients with poor OS to profiles associated with good OS. We found three compounds that convert the gene expression profiles of three HCC cell lines to gene expression profiles associated with good OS. These compounds increase histone acetylation, which correlates with the synergistic sensitization of those multidrug-resistant tumor cells to conventional chemotherapeutic agents including cisplatin, sorafenib and 5-fluorouracil. Our results indicate that it is possible to modulate gene expression profiles in HCC cell lines to those associated with better outcome. This approach also increases sensitization of HCC cells towards conventional chemotherapeutic agents. This work suggests new treatment strategies for a disease for which few therapeutic options exist. ER -