Cross-Species Functional Genomic Screens Identify Novel Therapeutic Targets in Malignant Peripheral Nerve Sheath Tumors.

Abstract

As oncogenic pathways are highly conserved in vertebrates, genetically engineered mouse models can potentially be used to identify therapeutic targets relevant to rare human cancers, such as malignant peripheral nerve sheath tumors (MPNSTs). To test this, genome-scale shRNA screens designed to identify genes driving proliferation and survival were performed in five MPNST cultures derived from P₀-GGFβ3 mice and three human MPNST cell lines. Several hundred gene hits mediating proliferation and survival were identified in human and mouse MPNST cells, many of which have been implicated in proliferation and survival in other cancers and/or mediate the pathogenesis of other cancer types. These hits and their associated signaling pathways extensively overlapped in human and mouse MPNST cells. A drug discovery pathway based on the Drug-Gene Interaction Database was developed to identify hits encoding druggable targets. Five druggable targets were selected for validation, with four of the five agents tested proving effective against human MPNST cells (the DNA polymerase α1 inhibitor clofarabine, the DNA nucleotidylexotransferase inhibitor cordycepin, the BCL6 inhibitor 79-6, and the lysophosphatidic acid receptor 1/3 inhibitor Ki16425). Clofarabine was especially effective, potently reducing cell numbers at low nanomolar concentrations and inducing a senescent phenotype, possibly via the p53/p21 pathway. These results demonstrate the utility of cross-species functional oncogenomics for the discovery of novel therapeutic targets relevant to human MPNSTs and suggest that clofarabine warrants further evaluation for its therapeutic potential.