PURPOSE: Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive 
tumor type that is resistant to chemotherapy and there are no effective 
therapies. MPNSTs have been shown to have gene amplification for receptor 
tyrosine kinases (RTK), PDGFR and c-Kit. We tested the c-Kit inhibitor, 
imatinib, and PLX3397, a selective c-Fms and c-Kit inhibitor, to evaluate their 
efficacy against MPNST cells in vitro and in vivo.
EXPERIMENTAL DESIGN: We tested the efficacy of imatinib or PLX3397 either alone 
or in combination with TORC1 inhibitor rapamycin in a cell proliferation assay 
in vitro and by immunoblotting to determine target inhibition. Immunoblotting 
and immunohistochemical analysis was further carried out using xenograft samples 
in vivo.
RESULTS: Our in vitro studies show that imatinib and PLX3397 similarly inhibit 
cell growth and this can be enhanced with rapamycin with comparable target 
specificity. However, in vivo studies clearly demonstrate that compared with 
imatinib, PLX3397 results in sustained blockade of c-Kit, c-Fms, and PDGFRβ, 
resulting in significant suppression of tumor growth. Moreover, staining for 
Iba-1, a marker for macrophages, indicates that PLX3397 results in significant 
depletion of macrophages in the growing tumors. The combination of PLX3397 and 
rapamycin results in even greater macrophage depletion with continued growth 
suppression, even when the drug treatment is discontinued.
CONCLUSIONS: Taken together, our data strongly suggest that PLX3397 is superior 
to imatinib in the treatment of MPNSTs, and the combination of PLX3397 with a 
TORC1 inhibitor could provide a new therapeutic approach for the treatment of 
this disease.