Multi-omics integration of malignant peripheral nerve sheath tumors nominates therapies based on chromosome 8q status

Chromosome 8q (chr8q) copy number gain is associated with high-grade transformation in malignant peripheral nerve sheath tumors (MPNST), an aggressive soft tissue sarcoma. To identify potential treatments for patients with chr8q gain, we leveraged our library of MPNST patient-derived xenografts (PDX) and collected global proteomics and phosphoproteomics measurements for six of these models. We integrated these data with transcriptomics and copy number data to identify the multiomics networks altered by chr8q status, which were then used to nominate drug candidates. Our results identify the chr8q gene MYC as a key driver of chr8q gain-related effects and suggest that these samples could be targeted with PLK1 inhibitors, while MPNSTs without MYC gain might benefit more from EGFR inhibition. We tested this hypothesis through in vitro validation, showing that multiomic integration can identify drug therapies to selectively target tumors based on genetic aberration, even in rare cancers where sample size is small.