Transcriptional response to PORCN inhibition using an in vivo model of RNF43 mutant pancreatic adenocarcinoma (HPAF-II) in EP300 knockout and WT cells

RNF43-mutant pancreatic tumors are driven by Wnt signaling and sensitive to Wnt inhibition, e.g. PORCN inhibitors. However, some RNF43-mutant pancreatic cancers are intrinsically resistant to Wnt inhibition. We identified that EP300 mutations confer resistance to PORCN inhibitors in RNF43-mutant pancreatic cancers. We found that EP300 knockout down-regulated GATA6 expression and GATA6-regulated differentiation program, making the anti-differentiation roles of Wnt signaling dispensable. To decipher the underlying drug resistance mechanisms, we performed transcriptome analysis in EP300 wildtype and knockout HPAF-II orthotopic xenografts treated with vehicle or PORCN inhibitor ETC-159 (5 mg/kg q.d. x 3 days or 15 mg/kg q.d. x 3days). Orthotopic tumors were harvested 8 hours post the last dose (56 hours of treatment). Total RNAs were extracted and subjected to RNA-seq.