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Identifying, Diagnosing, and Grading Malignant Peripheral Nerve Sheath Tumors in Genetically Engineered Mouse Models
08:57

Identifying, Diagnosing, and Grading Malignant Peripheral Nerve Sheath Tumors in Genetically Engineered Mouse Models

Published on: May 17, 2024

Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells

Grazia Ambrosini1, Haider S Cheema, Sharon Seelman

  • 1Laboratory of New Drug Development, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

Molecular Cancer Therapeutics
|April 17, 2008
PubMed

Insights

Malignant peripheral nerve sheath tumors (MPNSTs) show sensitivity to sorafenib, a B-Raf inhibitor. This drug targets the Ras/Raf/mitogen-activated protein kinase pathway, offering a potential new therapy for MPNST patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue tumors with poor prognosis and resistance to conventional chemotherapy.
  • MPNSTs are driven by Ras pathway activation, often due to loss of the neurofibromatosis type 1 tumor suppressor.
  • The Ras/Raf/mitogen-activated protein kinase (MAPK) pathway is a potential therapeutic target in MPNST.

Purpose of the Study:

  • To investigate the efficacy of sorafenib, a B-Raf inhibitor, in treating MPNST.
  • To elucidate the molecular mechanisms underlying sorafenib's action in MPNST cell lines.
  • To compare the response of MPNST cells to sorafenib with that of liposarcoma cells.

Main Methods:

  • Characterization of Ras activation and B-Raf expression in MPNST and liposarcoma cell lines.
  • Treatment of tumor cell lines with sorafenib and assessment of growth inhibition.
  • Analysis of downstream signaling molecules (phospho-MEK, phospho-ERK), cell cycle progression, and expression of cyclin D1 and pRb.
  • Validation using small interfering RNA (siRNA) to deplete B-Raf or C-Raf in MPNST cells.

Main Results:

  • MPNST cell lines exhibited sensitivity to sorafenib at nanomolar concentrations.
  • Sorafenib treatment inhibited phospho-MEK and phospho-ERK, suppressed cyclin D1, and induced G(1) cell cycle arrest via pRb hypophosphorylation.
  • Liposarcoma cell lines showed no significant response to sorafenib, correlating with low B-Raf expression or reduced Ras activation.
  • siRNA-mediated B-Raf depletion in MPNSTs mimicked sorafenib's effects, inducing G(1) arrest and inhibiting cyclin D1 and Rb phosphorylation, while C-Raf depletion had no effect.

Conclusions:

  • Sorafenib effectively inhibits MPNST cell growth by targeting the MAPK pathway.
  • The findings suggest that sorafenib is a promising novel therapeutic agent for MPNST.
  • B-Raf is a key mediator of MPNST proliferation, making it a viable therapeutic target.

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