Advanced-stage and recurrent granulosa cell tumors (GCT) of the ovary are poorly responsive to chemotherapies (1). We have previously shown that the human GCT KGN cell line exhibits a novel feed-forward loop between NFКB and SMAD2/3 signalling, which supports heightened cell survival (2). To determine whether overactivation of these pathways is found in the clinical disease, the current work evaluated the expression of NFКB p65, SMAD2, and SMAD3 in 18 GCT by immunohistochemistry. Nuclear localisation of each protein was determined as an index of pathway activation, and XIAP was evaluated in parallel as a known downstream target of NFКB/SMAD2/SMAD3 involved in chemoresistance (3). This analysis revealed that 100% of the GCT expressed XIAP. NFКB p65 was present in 17/18 samples, with 78% exhibiting nuclear and peri-nuclear staining. A vast majority of GCT (>78%) expressed SMAD2 and/or SMAD3, generally in both the cytoplasm and the nucleus of the tumour cells. Significantly, most GCT (72%) co-expressed XIAP, p65, SMAD2, and SMAD3. Using the KGN cell model, we investigated the contribution of these pathways in response to cisplatin, a common chemotherapeutic. KGN spheroids were poorly responsive to cisplatin (0.625-5 µg/ml), with only the highest dose resulting in significant cell death. Cisplatin dose-dependently decreased NFКB and SMAD3 reporter activity, suggesting that cisplatin suppresses KGN cell viability, at least in part, by countering the constitutive activity of these pathways. Co-treating KGN spheroids with cisplatin and either an NFКB inhibitor (BAY11-7082) or SMAD2/SMAD3 inhibitor (SB431542) increased GCT cell death by 200% (p<0.05). These studies indicate a mechanistic link between NFКB/SMAD2/SMAD3 activation and resistance to platinum-based therapies in GCT cells, supporting the utility of countering these pathways to sensitise GCT cells to traditional chemotherapies. Supported by funds from: CASS Foundation (MB); GCTRF (MB; KLS), NHMRC (338516; KLS, JKF), and Victorian Government's Operational Infrastructure Support Program.