Abstract Malignant peripheral nerve sheath tumor (MPNST) is a rare and highly aggressive tumor type that accounts for approximately 5-10% of soft tissue sarcomas. MPNSTs arise either spontaneously or in patients with type 1 neurofibromatosis (NF1). These tumors are highly resistant to chemotherapy and there are no effective treatment options. It has been demonstrated that MPNSTs with NF1 mutations are highly sensitive to the mTOR inhibitor rapamycin. However, inhibition of this pathway by rapamycin in sarcomas has been shown to release negative feedback inhibition of IGF-1R and activate AKT (pAKT). We have shown that treatment of MPNST cell lines (MPNST and ST8814) with rapamycin activates AKT, but not through IGF-1R, since IGF-1R is not expressed in these cells. This would suggest an alternate route for rapamycin induced AKT activation. To understand this process, we treated MPNST and ST8814 cells, with or without rapamycin, and used cellular lysates to determine whether the release of negative feedback by mTOR inhibition was mediated by alternate receptor tyrosine kinases (RTKs). Using RTK array profiling (R&D Systems), our results indicate that both p-PDGFRα and p-PDGFRß are activated in response to rapamycin. Using imatinib (STI571) to target both PDGFRα and PDGFRß, we show that imatinib blocks rapamycin induced reactivation of pAKT. In order to rule out off target effects of imatinib, knockdown of PDGFR using siRNA followed by treatment with rapamycin recapitulates the effects observed with imatinib treatment. The combination of imatinib and rapamycin in MPNST cells resulted in a significant decrease in cell proliferation when compared to either of the two drugs alone. Mouse xenograft studies also show that tumor growth volume is decreased significantly when xenografts are treated with imatinib in combination with rapamycin compared to either drug alone. Taken together, our data strongly suggests that in MPNST cells, PDGFR pathway is involved in rapamycin mediated release of the negative feedback loop that activates pAKT. Furthermore, the targeting of PDGFR in combination with inhibitors of mTOR could provide a new therapeutic approach for the treatment of this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1224. doi:1538-7445.AM2012-1224