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Receptor tyrosine kinase pathway analysis sheds light on similarities between clear-cell sarcoma and metastatic

Tiziana Negri1, Silvia Brich, Elena Conca

  • 1Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Genes, Chromosomes & Cancer
|November 3, 2011
PubMed

Insights

Clear-cell sarcoma (CCS) and metastatic melanoma (MM) share similar receptor tyrosine kinase (RTK) pathway activation. BRAF mutations and chromosome aberrations in EWSR1- CCS suggest potential therapeutic targets, including RON inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Clear-cell sarcoma (CCS) and metastatic melanoma (MM) are distinct malignancies.
  • Understanding their molecular signaling pathways can reveal therapeutic vulnerabilities.

Purpose of the Study:

  • To compare receptor tyrosine kinase (RTK) and downstream signaling activation profiles between CCS and MM.
  • To identify potential therapeutic targets for CCS based on similarities with MM.

Main Methods:

  • Investigated frozen and fixed samples from CCS (with and without EWSR1 rearrangement) and MM using biochemical, immunohistochemical, FISH, molecular analyses, and immunofluorescence microscopy.
  • Sequenced BRAF, NRAS, and KRAS mutations and performed FISH for chromosome 22 and 8 gains in additional samples.

Main Results:

  • Both CCS and MM showed activation of short-form recepteur d'origine nantais (RON) RTK, PDGFRB, MET, and HER3.
  • Consistent downstream signaling phosphorylation patterns of PI3K/AKT, RSK, and mTOR targets (S6, 4EBP1) were observed.
  • BRAF V600E mutation was found in a subset of CCS (EWSR1+ and EWSR1-), and a significant correlation between chromosome 22 and 8 gains and EWSR1- CCS was identified.

Conclusions:

  • BRAF mutations can occur in CCS, and chromosome 22/8 aberrations may serve as a hallmark for EWSR1- CCS.
  • Similarities in RTK pathway activation between CCS and MM suggest that therapies effective in melanoma, particularly RON inhibitors, could be beneficial for CCS treatment.

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