Shh pathway activation drives malignant transformation in a subset of mpnsts and is a potential therapeutic target

Abstract BTFC travel award recipient Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann-cell derived sarcomas and the leading cause of mortality in Neurofibromatosis Type 1. The molecular pathways driving malignant transformation is not well understood. In this study, we leveraged multi-platform genomic and epigenomic profiling of human neurofibromas and MPNSTs to identify targetable molecular pathways that lead to malignant transformation. Fresh-frozen tumors (N = 108) were studied including methylation profiling, RNA sequencing, and whole exome sequencing. Unsupervised consensus clustering of methylome and transcriptome data identified 2 distinct MPNST subgroups. Pathway analysis showed that MPNST-G1 tumors are characterized by SHH pathway activation (NES=1.9952, p<0. 0001, FDR<0.001), while MPNST-G2 tumors are characterized by WNT pathway activation (NES=1.7630, p<0.0001, FDR=0.0058). We observed significantly higher rates of PTCH1 deletions, a negative regulator of SHH pathway, in MPNST-G1 (62.5% vs 0%, Fisher Exact Test=0.0065, p<0.05) and PTCH1 promoter hypermethylation (mean beta value: 0.2899 vs. 0.06119, p<0.05). A computational drug screen identified sonedigib, a SHH pathway inhibitor, as a potential treatment option for MPSNT-G1. We validated the importance of SHH pathway in malignant transformation by knocking out PTCH1 in neurofibroma cell lines and demonstrated increased cellular proliferation, cellular migration and invasion. In addition, treatment with sonedigib decreased cellular viability in MPNST cell lines and improved survival in mouse xenograft models. These results suggest a targeted approach should be taken for treating MPNSTs, and SHH and WNT pathway inhibition may be promising avenue for therapeutic development.