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The PI3K AKT mTOR signaling axis has received much attention in recent years given its potential role in cancer. This critical pathway acts as a convergence point for a multitude of upstream signals and in turn stimulates the activity of numerous downstream effectors, thereby mediating enhanced cellular survival, growth, protein synthesis, motility and other functions mapk inhibitor of pro tumorigenic impact. Consequently, it is not surprising that deregulation and aberrant activation of the PI3K/AKT/mTOR signaling axis componentry is a common molecular event in a wide range of malignancies. These insights have led to the development of novel therapies targeting single or multiple constituents of this pathway, several are currently in clinical evaluation. Multiple lines of evidence strongly support a role for deregulated PI3K/AKT/mTOR signaling in MPNST. Studies from our laboratory have recently shown enhanced expression of the activated AKT and mTOR downstream Papillary thyroid cancer effectors S6RP and 4EBP1 in a relatively large cohort of human MPNST specimens as well as in human tumor derived cell lines. Aberrant PI3K/AKT/mTOR signaling in MPNST is mediated by the loss of neurofibromin function, the critical molecular event responsible for NF1, as recently demonstrated in genetically engineered mouse models. Loss of function Nf1 mutations have also been identified in a portion of sporadic MPNSTs. The Nf1 protein is a known RAS GAP, consequently, Nf1 loss in constitutive RAS activation leading to enhanced downstream PI3K/AKT/mTOR signaling. Other MPNST associated deregulations possibly contributing to the noted constitutive activation of this axis include the common overexpression and aberrant signaling of multiple upstream tyrosine kinase receptors as well as loss of the PI3K inhibitor, PTEN, which has recently been shown as contributory to MPNST malignant transformation. These insights highlight the relevance of Dovitinib the PI3K/AKT/mTOR axis as a potential novel target for anti MPNST therapy. Pre clinical studies using rapamycin or its derivatives have yielded promising . MPNST cells isolated from NF1 patients were found to be highly sensitive to rapamycin which was also found to effectively abrogate tumor growth in MPNST GEMMs. Furthermore, the rapamycin analogue RAD001 inhibited the growth of human NF1 associated and sporadic MPNST cells, RAD001 treatment of human MPNST xenografts significantly delayed tumor growth. These findings form the rationale for several currently ongoing clinical trials to assess the effect of such inhibitors in patients with nonoperable NF1 associated neurofibromas and/or those with advanced MPNST. However, accumulating data from other solid malignancies suggest that the clinical effects of mTORC1 inhibitors are at best cytostatic, resulting in transient tumor stabilization with evidence of re growth during and/or after treatment discontinuation.