Wnt-driven chromosomal instability as a biomarker for PORCN inhibition

Targeting Porcupine (PORCN), a key regulator of the WNT-signalling pathway, has shown therapeutic potential in multiple cancers. However, clinical responses to PORCN inhibitors have so far been limited despite strong target engagement data and a favourable safety profile. Given that Wnt signaling can drive tumorigenesis by inducing chromosomal instability (CIN), we hypothesised that CIN signatures might serve as a novel predictive biomarker to improve PORCN inhibitor response rates. Using a combination of CIN signatures capturing diverse Wnt-driven CIN processes including replication stress, error-prone non-homologous end joining repair, and whole genome duplication, we established proof-of-concept of a biomarker predictive of PORCN inhibition response. We found that CIN signature activity significantly correlated with both knockdown and pharmacological inhibition of PORCN across 180 and 24 cancer cell lines, respectively (Kendall's Tau=-0.16, P-value=0.001,Tau=-0.22, P-value=0.065). We performed a meta-analysis of 25 studies of in vivo patient-derived or cell-line xenografts treated with PORCN inhibitors, and found that biomarker activity was quantitatively associated with response to PORCN inhibition, (CIN signature activity versus tumour over control ratio, Pearson's R=-0.66, P-value=0.009). Using these data to determine an optimised threshold for clinical application (specificity=100%, 95%CI:54.07%-100% and sensitivity=100%, 95%CI:29.24%-100%), we showed concordance between predicted and observed efficacy in previous PORCN inhibitor clinical trials. The quantitative nature of the CIN signature biomarker offers an opportunity to widen the therapeutic index of existing clinical stage PORCN inhibitors and analysis of biomarker prevalence across 6,335 patient tumours from The Cancer Genome Atlas study identifies esophageal and gastric cancers as optimal indications for future clinical development.