Inhibition of isoprenylcysteine carboxylmethyltransferase (lcmt), which catalyzes the final step of oncoproteins' prenylation, targets growth and survival of various cancers. In this work, we systematically studied the expression, functions and molecular signaling of lcmt in ovarian cancer. We show that the upregulation of Icmt expression is a common feature in patients with epithelial ovarian cancer regardless of age and disease stage. In line with the observations in ovarian cancer patients, a panel of epithelial ovarian cancer cell lines also demonstrates the significant increase on lcmt transcript and protein levels than normal ovarian epithelial cells. In addition, ovarian cancer cell lines with higher lcmt levels are more resistant to chemotherapeutic agents. We further show that Icmt inhibition by siRNA or inhibitor cysmethynil suppresses growth and induces apoptosis in ovarian cancer cells. Importantly, lcmt inhibition significantly augments chemotherapeutic agent's efficacy in vitro and in vivo, demonstrating the translational potential of lcmt inhibition in ovarian cancer. Mechanistically, we show that Ras activation is a critical effector of lcmt in ovarian cancer cells. Using cell culturing system, mouse model and patient samples, our work is the first to demonstrate the essential roles of Icmt in ovarian cancer via Ras signaling, particularly on its response to chemotherapy. Our findings suggest that lcmt inhibition is a promising therapeutic strategy to overcome chemoresistance in ovarian cancer, in particular, those patients with high lcmt expression. (C) 2018 Elsevier Inc. All rights reserved.