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Research Articles: Therapeutics, Targets, and Development

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

¹ Laboratory of New Drug Development, Department of Medicine, and ² Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Gary K. Schwartz, Laboratory of New Drug Development, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-8324; Fax: 212-717-3320. E-mail: schwartg{at}mskcc.org

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue tumors with a very poor prognosis and largely resistant to chemotherapy. MPNSTs are characterized by activation of the Ras pathway by loss of tumor suppressor neurofibromatosis type 1. In view of this, MPNST may be susceptible to inhibition of the activated Ras/Raf/mitogen-activated protein kinase pathway by the B-Raf inhibitor sorafenib. MPNST (MPNST and ST8814) and dedifferentiated liposarcoma (LS141 and DDLS) human tumor cell lines were characterized for Ras activation and B-Raf expression. Tumor cells were treated with sorafenib and examined for growth inhibition, inhibition of phospho-MEK, phospho-ERK, cell cycle arrest, and changes in cyclin D1 and pRb expression. MPNSTs were sensitive to sorafenib at nanomolar concentrations. This appeared to be due to inhibition of phospho-MEK, phospho-ERK, suppression of cyclin D1, and hypophosphorylation of pRb at the CDK4-specific sites, resulting in a G₁ cell cycle arrest. These effects were not seen in the liposarcoma cells, which either did not express B-Raf or showed decreased Ras activation. Small interfering RNA–mediated depletion of B-Raf in MPNSTs also induced a G₁ cell cycle arrest in these cells, with a marked inhibition of cyclin D1 expression and Rb phosphorylation, whereas depletion of C-Raf did not affect either. With growth inhibition at the low nanomolar range, sorafenib, by inhibiting the mitogen-activated protein kinase pathway, may prove to be a novel therapy for patients with MPNST. [Mol Cancer Ther 2008;7(4):890–6]

Grant support: Soft Tissue Sarcoma Program Project PO1 CA047179, Kristin Ann Carr Fund, and NIH T32 training grant CA09501 (E.B. Sambol).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/ 1/07; revised 12/11/07; accepted 2/20/08.