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Spitz tumors and melanomas with MET fusion

ABSTRACT: Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumors with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumors lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K), and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist.

ORGANISM(S): Homo sapiens

PROVIDER: GSE67841 | GEO | 2015/12/01

SECONDARY ACCESSION(S): PRJNA281056

REPOSITORIES: GEO

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Project description:With the advent of potent second-line anti-androgen therapy, we and others have observed an increased incidence of androgen receptor (AR)-null small cell or neuroendocrine prostate cancer (SCNPC) in metastatic castration-resistant prostate cancer (mCRPC). Additionally, we have detected upregulated expression of MET and RET transcripts in SCNPC metastases relative to adenocarcinoma. Our study was designed to determine the effect of cabozantinib, a multi-targeted tyrosine kinase inhibitor that inhibits MET, RET and VEGFR2, on SCNPC patient-derived xenografts (PDX) in vivo. Surveillance of SU2C and University of Washington rapid autopsy mCRPC cohorts through RNA-Seq revealed that increased MET expression significantly correlated with loss of AR expression and activity. In vitro treatment of SCNPC PDX cells with AMG 337 had no impact on cell viability in LuCaP 93 (MET+/RET+) and LuCaP 173.1 (MET-/RET-), whereas cabozantinib decreased cell viability in LuCaP 93, but not in LuCaP 173.1. Notably, tumor volume was significantly decreased (p<0.001) with cabozantinib treatment in SCID mice bearing LuCaP 93 and LuCaP 173.1 tumors. Tissue analysis indicated that tumor cell proliferation was not inhibited by cabozantinib, but that cabozantinib decreased microvessel density (CD31) in LuCaP 93 (p<0.001) and LuCaP 173.1 (p<0.01) tumors. RNA-Seq and gene set enrichment analysis determined that hypoxia and glycolysis pathways were increased in cabozantinib treated tumors relative to control tumors. Thus, cabozantinib inhibited tumor growth in MET+/RET+ LuCaP 93 and MET-/RET- LuCaP 173.1 tumors in vivo and this activity was independent of MET or RET expression in LuCaP 173.1. Our data suggest that the most likely mechanism of tumor growth suppression is through disruption of the stromal architecture and cabozantinib may represent a potential therapy for patients with metastatic disease in tumor phenotypes that have a significant dependence on the tumor vasculature for survival and proliferation.

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Spitz tumors and melanomas with MET fusion

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