Pancreatic adenocarcinoma (PDAC) is marked by very low survival rates, as well as by the lack of effective therapies, with resistance a major cause of clinical treatment failure. A key feature of PDAC is the presence of a dense fibrous stroma, which can comprise up to 90% of the mass of the PDAC tumours (1-4). The dynamic signalling that occurs between tumour cells and the diverse cells of the surrounding tumour microenvironment actively promotes disease progression and therapeutic resistance (1-6). Personalized cancer therapies targeting patient-specific mutations, and which can be used in combination with conventional chemotherapy, are a way forward on the path to improved survival.
RNF43 is an E3 ligase which negatively regulates Wnt signalling by targeting Wnt ligands for degradation. Whereas loss-of-function mutations in RNF43 may drive cancer progression by increased Wnt pathway activity, evidence suggests that cancers with RNF43 mutations are sensitive to pharmacological Wnt inhibition. A subset of PDAC cases carry RNF43 mutations and may respond to Wnt inhibitors (7).
RXC004 is a selective and potent inhibitor of the Porcupine protein. Porcupine is an O-palmitoleoyltransferase which activates Wnt ligands, and whose inhibition suppresses both canonical and non-canonical Wnt pathways (7). Previous work has demonstrated that RXC004 reduces disease progression in cancers carrying RNF43 mutations (7).
Excitingly, we have demonstrated that RXC004 alone can reduce tumor growth in murine models of PDAC, and alters tissue morphology, markers of proliferation and apoptosis, and ECM components such as collagen, fibronectin, and periostin in vivo. Spatial alterations in α-smooth muscle actin expression point to differences in cancer associated fibroblast (CAF) activation and changes to CAF subpopulations which may underlie key tumor-stroma interactions which modulate cancer response to therapy. Additionally, RXC004 in combination with chemotherapy in orthotopic mouse models of PDAC increases survival.
Future studies will utilize cutting-edge spatial transcriptomic tools to investigate the effect of porcupine inhibition in RNF43 mutant models in vivo, and also determine the applicability of RXC004 in the context of chemoresistance.