e14094 Background: Wnt signalling initiates oncogenic pathways involved in tumour initiation, growth, differentiation and metastasis.1 Targeting the Wnt pathway is an attractive approach to cancer treatment. Porcupine (PORCN) is a membrane-bound O-acyltransferase dedicated to the palmitoylation of Wnt ligands, an essential step in the processing of Wnt into active ligands.2 A PORCN inhibitor may benefit patients with cancers in which Wnt signalling is implicated. It has been shown that PORCN inhibition is efficacious in cell lines with upstream mutations in this pathway, eg RNF43 loss of function.3 Methods: Analysis of TCGA data was carried out to identify cancer types harbouring RNF43 mutations.4 Redx PORCN inhibitor RXC004 was evaluated in vitro for Wnt pathway inhibition and anti-proliferative effects using assays previously described for early lead compounds.5Anti-tumour effects of RXC004 were evaluated using a pancreatic CAPAN-2 xenograft in SCID Bg. mice and a gastric PDX model in nu/nu mice. Both models have RNF43 loss of function mutations. Results: TCGA data revealed that both gastric cancer and pancreatic cancer exhibit mutations in the RNF43 gene (18% and 4% respectively),4expected to result in loss of function. RXC004 showed activity in preclinical models of cancers with this genetic background. RXC004 significantly inhibited tumour growth in a CAPAN-2 pancreatic cancer xenograft and in a gastric cancer PDX model when dosed orally once or twice daily. Conclusions: Taken together, these data indicate that RXC004 is a potent inhibitor of tumour growth in RNF43 loss of function preclinical cancer models. RXC004 will be evaluated in a first in human Phase 1 study in 2017. Phase 1a aims are to characterise the safety profile and PK/PD relationship in cancer patients and establish a Phase 1b dose. The efficacy of RXC004 in gastric and pancreatic cancer patients prospectively selected for RNF43 loss of function mutations will be the focus of Phase 1b expansion groups. 1 . Nat. Rev. Cancer, 2013, 13 (1): 11-26.2. J. Biol. Chem., 2012, 287 (27): 23246-23254. 3. PNAS, 2013, 110 (31): 12649-12654 4. Sci. Signal, 2013, 269 (6): 1-34; Cancer Discov., 2012, 2 (5): 401-404 5. AACR Annual Meeting, 2015, 75 (15): abs. 5071.