High prevalence of mTOR complex activity can be targeted using Torin2 in papillary thyroid carcinoma. a second-generation mTOR inhibitor, Torin2, on a panel of EOC cell lines. Torin2 treatment decreased cell viability and induced apoptosis in a dose-dependent manner via inactivation of mTORC1 and mTORC2 and their downstream targets in EOC cell lines. Furthermore, treatment of EOC cells with a subtoxic dose of Torin2 potentiated a cisplatin-induced apoptotic response in Mouse monoclonal to CD32.4AI3 reacts with an low affinity receptor for aggregated IgG (FcgRII), 40 kD. CD32 molecule is expressed on B cells, monocytes, granulocytes and platelets. This clone also cross-reacts with monocytes, granulocytes and subset of peripheral blood lymphocytes of non-human primates.The reactivity on leukocyte populations is similar to that Obs EOC cell lines. Finally, we studied the effect of a combination of Torin2 and cisplatin and found that this combination synergistically inhibited tumor growth in nude mice. These studies highlight the importance of targeting the mTOR survival pathway and suggest that cotreatment with cisplatin and Torin2 may be beneficial for the management of EOC. INTRODUCTION Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in the world (1). EOC is a heterogeneous disease that spreads rapidly if untreated (2). EOC usually presents as a late-stage disease due to a lack of symptoms to diagnose the cancer at an early stage (3). As EOC usually presents as a late-stage disease, the treatment protocol commonly used STAT3-IN-1 is cytoreduction and debulking of the tumor by surgery followed by platinum-based chemotherapy along with paclitaxel (4). Even though the surgical protocols as well as the treatment for EOC have improved tremendously over the last decade (4), 50% of the patients that present with late-stage disease will eventually relapse or die (5). Therefore, there is an urgent need to improve the overall survival of patients diagnosed with EOC. Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that controls cell survival and growth and is often found to be dysregulated in many diseases (6,7,8). mTOR functions by forming two different protein complexes; mTORC1 and mTORC2 (9). mTORC1 is rapamycin sensitive and is dependent upon changes in oxygen levels, stimulation by growth factors and STAT3-IN-1 changes in nutrients status (10). A critical function of mTORC1 is to regulate protein synthesis STAT3-IN-1 via a number of substrates, including p70S6 kinase, the inhibitory eIF4E- binding proteins (4E-BPs) and the eIF4G initiation factors (11,12). mTORC2 is rapamycin resistant and is not dependent on nutrients and is responsible for cancer cells growth and proliferation even in extreme conditions such as lack of nutrients and energy (9). The functionality of the mTORC2 complex is facilitated mainly by activation of AKT at site Ser473. Once AKT is activated, it leads to cell survival, proliferation and growth (12,13,14). It is an accepted fact that AKT is found to be constitutively activated in a variety of cancers (15,16,17), therefore, for efficient treatment of cancer, it is very important that both mTOR complexes are targeted simultaneously to achieve an anticancer effect (13). Clinical trials using newer generation mTOR inhibitors have shown the efficacy and utility of targeting mTOR pathways for the management of various cancers (18,19,20). These trials have paved the way for using mTOR inhibitors for the treatment of advanced stage renal cell carcinoma and breast cancer (21,22). Even though there has been success in treating advanced stage cancers with mTOR inhibitors, most of the first generation mTOR inhibitors have the propensity to target the mTORC1 complex and it has been shown that by not targeting the mTORC2 complex, resistance against these inhibitors quickly develops via activation of AKT at phosphorylation site Ser473 (23,24,25). Torin2, a second generation mTOR inhibitor, has the ability to target and inhibit both the mTOR complexes efficiently and therefore has an edge over other first generation inhibitors in effectively inhibiting mTOR activity and inducing apoptosis in cancer cells (26,27,28). Platinum resistance is a major obstacle in the treatment of ovarian cancer. Even though most ovarian cancers respond to initial platinum-based chemotherapy, more than 50% STAT3-IN-1 of these cancers eventually relapse. Relapse in ovarian cancer cases can be classified in three groups: platinum refractory if the cancer relapses within a month of treatment or if the disease progresses despite platinum-based therapy; platinum resistant if the cancer relapses within 6 months of treatment; and platinum sensitive if the cancer relapses after 6 months of initial treatment (29). There are.