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PDF file - 107KB, Two class comparison between combination treated samples and controls for the other GLUT proteins and hexokinses. The log2 of fold (combination/control) expression for each gene in the GLUT and hexokinase family are shown, such that negative values indicate a decrease in the combination relative to control, and positive values represent an increase. The p-value for the difference in expression between classes is shown.

PDF file - 47KB, Supplementary Figure 1 shows that AKT inhibition does not slow proliferation in a human MPNST cell line.

PDF file - 75KB, Reported in vitro isoform specificities of PI3K inhibitors. The IC50 (nM) reported in the literature for each PI3K inhibitor against Class IA catalytic isoforms in in vitro binding assays is shown. The source for each data set is listed. A66-(S) is termed a p110alphaspecific inhibitor, AZD-6482 is classified as a p110beta-specific inhibitor, and CAL-101 shows selectivity for p110delta. GDC-0941 does not show significant isoform selectivity.

PDF file - 58KB

NF1 encodes a RAS GTPase-activating protein. Accordingly, aberrant RAS activation underlies the pathogenesis of NF1-mutant cancers. Nevertheless, it is unclear which RAS pathway components represent optimal therapeutic targets. Here, we identify mTORC1 as the key PI3K effector in NF1-mutant nervous system malignancies and conversely show that mTORC2 and AKT are dispensable. However, we find that tumor regression requires sustained inhibition of both mTORC1 and MEK. Transcriptional profiling studies were therefore used to establish a signature of effective mTORC1–MEK inhibition in vivo. We unexpectedly found that the glucose transporter GLUT1 was potently suppressed, but only when both pathways were inhibited. Moreover, unlike VHL- and LKB1-mutant cancers, reduction of 18F-FDG uptake required the suppression of both mTORC1 and MEK. Together, these studies identify optimal and suboptimal therapeutic targets in NF1-mutant malignancies and define a noninvasive means of measuring combined mTORC1–MEK inhibition in vivo, which can be readily incorporated into clinical trials. Significance: This work demonstrates that mTORC1 and MEK are key therapeutic targets in NF1-mutant cancers and establishes a noninvasive biomarker of effective, combined target inhibition that can be evaluated in clinical trials. Cancer Discov; 4(9); 1062–73. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 973

SummaryLoss-of-function mutations in the NF1 tumor suppressor result in deregulated Ras signaling and drive tumorigenesis in the familial cancer syndrome neurofibromatosis type I. However, the extent to which NF1 inactivation promotes sporadic tumorigenesis is unknown. Here we report that NF1 is inactivated in sporadic gliomas via two mechanisms: excessive proteasomal degradation and genetic loss. NF1 protein destabilization is triggered by the hyperactivation of protein kinase C (PKC) and confers sensitivity to PKC inhibitors. However, complete genetic loss, which only occurs when p53 is inactivated, mediates sensitivity to mTOR inhibitors. These studies reveal an expanding role for NF1 inactivation in sporadic gliomagenesis and illustrate how different mechanisms of inactivation are utilized in genetically distinct tumors, which consequently impacts therapeutic sensitivity.