Efficacy of the Porcupine inhibitor RXC004 in genetically-defined tumour types


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Simon Woodcock1,Catherine Eagle1,Alicia Edmenson Cook1,Richard Armer1,Inder Bhamra1,Caroline Phillips1
1Redx Pharma

Abstract

Background

Potent and selective porcupine (PORCN) inhibitor RXC004 is being investigated in a Phase 1 clinical trial (CT 2017-000720-98). PORCN is a membrane bound O-acyltransferase responsible for post-translational modification of Wnt ligands, essential for Wnt secretion and activity. Wnt pathway alterations, including RNF43 loss-of-function mutations and RSPO fusions, result in increased levels of surface Fzd receptors, increasing Wnt-ligand dependent signalling. These alterations are implicated in colorectal, gastric, pancreatic and biliary cancer. This work assesses the direct tumour targeting effects of RXC004 in genetically selected cancer lines in vitro and in vivo.

Method

RXC004 was evaluated in 2D and/or 3D in vitro proliferation assays across a panel of colorectal and pancreatic cancer cell lines. In parallel, cell cycle analysis was assessed using flow cytometry. Downstream markers of target engagement for the Wnt pathway, Axin2 and c-Myc, were analysed for mRNA expression using qPCR. RXC004 was orally dosed for efficacy, PK and PD studies in RNF43 mutant and RSPO fusion xenograft models.

Results

RXC004 potently inhibited proliferation in vitro in several genetically selected cell lines. Mechanistically RXC004 arrested the cell cycle at the G1/S and G2/M cell cycle checkpoints. Axin2 mRNA expression was potently inhibited by RXC004 (sub-nM) across all RNF43 mutant and RSPO fusion cell lines tested. Furthermore, inhibition of c-Myc expression correlated with the anti-proliferative effects of RXC004. In contrast, RXC004 had no anti-proliferative effects on APC mutant colorectal cancer cells, and Axin2 and c-MYC expression was not inhibited. In vivo, RXC004 demonstrated significant efficacy and PD responses in multiple RNF43 mutant and RSPO fusion xenograft models.

Conclusion

Cancer cells carrying RNF43 mutations or RSPO fusions are sensitive to RXC004 both in vitro and in vivo. This data suggest RXC004 monotherapy would benefit patients with tumours baring RNF43 mutations or RSPO fusions and support a genetically-defined patient selection strategy for ongoing RXC004 clinical studies.