Integrating analysis of proteome profile and drug screening identifies therapeutic potential of MET pathway for the treatment of malignant peripheral nerve sheath tumor.

ABSTRACT

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with a poor prognosis that requires novel therapeutic agents. Proteome information is useful for identifying new therapeutic candidates because it directly reflects the biological phenotype. Additionally, in vitro drug screening is an effective tool to identify candidate drugs for common cancers. Hence, we attempted to identify novel therapeutic candidates for MPNST by integrating proteomic analysis and drug screening. METHODS: We performed comprehensive proteomic analysis on 23 MPNST tumor samples using liquid chromatography - tandem mass spectrometry to identify therapeutic targets. We also conducted drug screening of six MPNST cell lines using 214 drugs. RESULTS: Proteomic analysis revealed that the MET and IGF pathways were significantly enriched in the local recurrence/distant metastasis group of MPNST, whereas drug screening revealed that 24 drugs showed remarkable antitumor effects on the MPNST cell lines. By integrating the results of these two approaches, MET inhibitors, crizotinib and foretinib, were identified as novel therapeutic candidates for the treatment of MPNST. CONCLUSIONS: We successfully identified novel therapeutic candidates for the treatment of MPNST, namely crizotinib and foretinib, which target the MET pathway. We hope that these candidate drugs will contribute to the treatment of MPNST.