222P Therapeutic opportunities for porcupine inhibition in gastrointestinal cancer

Abstract

Background Gastrointestinal (GI) cancer (Upper/Lower GI and Hepatobiliary) causes more cancer deaths than any other body system. Wnt pathway activation promotes common GI cancers, but safely targeting this pathway is challenging. Inhibition of Porcupine, an enzyme essential for Wnt ligand activity, has clinical potential to suppress Wnt in a safe and tolerated manner. Preclinically, GI tumors with upstream Wnt pathway variants (RNF43 loss of function (LoF), RSPO gain of function (GoF)) are Wnt ligand dependent and exquisitely sensitive to RXC004, a small molecule Porcupine inhibitor. Using Caris data, 278,649 human tumor samples (across all 58 solid tumor lineages) were analysed for the prevalence of upstream Wnt pathway variants and associated features. Methods Human tumors were analysed by next-generation sequencing of DNA (592 genes, NextSeq; WES, NovaSeq) and RNA (WTS, NovaSeq) by Caris. Molecular profiles and prevalence of RNF43_LoF and RSPO2/3_GoF cases were compared with negative (WT) cases using Fisher-Exact analysis. Real world overall survival was obtained from insurance claims data and Kaplan-Meier estimates were calculated for defined cohorts from time of tissue collection to last contact. Results Prevalence of RNF43_LoF, RSPO2_GoF and RSPO3_GoF were 1.3%, 0.1% and 0.3% in all lineages; increasing to 3.6%, 0.2% and 0.9% in GI lineages. The top lineages by combined Wnt ligand dependent prevalence were GI: Small Bowel (9.6%), Colorectal (CRC; 5.9%), Pancreatic (5.4%) and Gastric (4.3%) cancers. Of 15,025 CRC cases, 13,886 (92%) were Microsatellite stable (MSS). Within MSS CRC cases, prevalence of RNF43_LoF was 2.6% and RSPO2/3_GoF was 1.6%; hence total prevalence was 4.2%. BRAF_V600E had high co-occurrence with Wnt ligand dependent (42%), compared to WT (3.4%), MSS CRC cases. In MSS CRC, upstream Wnt pathway variants were associated with poor prognosis in either all cases (HR 1.64; p<0.0001) or BRAF_WT cases (HR 1.52; p<0.0001) versus WT cases. Conclusions Upstream Wnt pathway variants are enriched in GI cancer, in particular Small Bowel cancer, a rare subtype of high unmet need. In MSS CRC cancer, the poor prognosis and high BRAF_V600E co-occurrence with upstream Wnt pathway variants suggests benefit of co-targeting Wnt and MAPK pathways in this population.