Data from Phenotypic Reversion of Invasive Neurofibromin-Deficient Schwannoma by FTS: Ras Inhibition Reduces BMP4/Erk/Smad Signaling

Neurofibromin-deficient (Nf1^−/−) malignant peripheral nerve sheath tumors (MPNST) are highly invasive, refractory to chemotherapy, and characterized by overactivated Ras. Ras activates mitogenic pathways and regulates morphogenic programs—such as those induced by bone morphogenetic proteins (BMP) and TGF-β. The role of such a cross-talk in determining the phenotype and transformation potential of MPNSTs is unknown. Here, we used MPNST cell lines and selective Ras inhibition with S-trans,trans-farnesylthiosalicylic-acid (FTS; salirasib) in conjunction with specific inhibitors of TGF-β and BMP signaling. FTS perturbed signaling of BMP4 and TGF-β1 to Smad-dependent and Erk-dependent pathways. Furthermore, FTS inhibited motility and spreading, reduced the gelatinase secretion, eliminated the expression and activation of regulators of cell–matrix interaction, and altered gene expression. These phenomena are indicative of a phenotypic reversion of NF1-defficient cells by FTS. Inhibition of BMP4 and TGF-β by noggin and SB-431542, respectively, mimicked the FTS-mediated effects on adhesion, spreading, and cell morphology. This strongly suggests that a cross-talk among TGF-β superfamily ligands and Ras plays a significant role in the transformation of NF1^−/− MPNSTs. Our results support the therapeutic potential of FTS, in conjuncture with BMP and TGF-β pathway inhibitors, toward the inhibition of mitogenic and morphogenic signaling pathways and the alleviation of NF1 symptoms. Mol Cancer Ther; 10(8); 1317–26. ©2011 AACR.