TORC1 Is Essential for NF1-Associated Malignancies

Abstract

Inactivating mutations in NF1 underlie the prevalent familial cancer syndrome neurofibromatosis type 1 [1]. The NF1-encoded protein is a Ras GTPase-activating protein (RasGAP) [2]. Accordingly, Ras is aberrantly activated in NF1-deficient tumors; however, it is unknown which effector pathways critically function in tumor development. Here we provide in vivo evidence that TORC1/mTOR activity is essential for tumorigenesis. Specifically, we show that the mTOR inhibitor rapamycin potently suppresses the growth of aggressive NF1-associated malignancies in a genetically engineered murine model. However, in these tumors rapamycin does not function via mechanisms generally assumed to mediate tumor suppression, including inhibition of HIF-1alpha and indirect suppression of AKT, but does suppress the mTOR target Cyclin D1 [3]. These results demonstrate that mTOR inhibitors may be an effective targeted therapy for this commonly untreatable malignancy. Moreover, they indicate that mTOR inhibitors do not suppress all tumor types via the same mechanism, suggesting that current biomarkers that rely on HIF-1alpha suppression may not be informative for all cancers. Finally, our results reveal important differences between the effects of mTOR inhibition on the microvasculature in genetically engineered versus xenograft models and indicate that the former may be required for effective preclinical screening with this class of inhibitors.

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

“…mTORC1 activation has also been implicated in MPNST tumorigenesis (33). Although mTORC1 inhibitors have shown some success in NF1 patients (40,41), tumor regression did not occur via the usual mechanisms, with the proangiogenic factor HIF1a remaining elevated under rapamycin treatment (33). Of interest, we also observed that HIF1a protein levels were not completely ablated with rapamycin treatment in all four MPNST cell lines tested.…”

“…8 for signaling diagram). mTORC1 activation has also been implicated in MPNST tumorigenesis (33). Although mTORC1 inhibitors have shown some success in NF1 patients (40,41), tumor regression did not occur via the usual mechanisms, with the proangiogenic factor HIF1a remaining elevated under rapamycin treatment (33).…”

“…A recent study indicated that HIF1a expression levels in MPNSTs were fairly resistant to mTORC1 inhibition with rapamycin (33), indicating that mTORC1 is less involved in promoting HIF1a in MPNSTs. We therefore hypothesized that JAK2/STAT3 might be the dominant pathway that promotes signal transduction through HIF1a in MPNSTs.…”

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

“…Indeed, the simultaneous activation and intrafamily functional redundancy of Ras proteins in NF1-null MPNST cells suggests that it will be difficult to target these proteins therapeutically. Consequently, some laboratories have asked whether targeting signaling pathways downstream of Ras such as mitogen-activated protein extracellular signal-related kinase (ERK) kinase (MEK) 31,32 and the phosphatidylinositol 3-kinase (PI3K)-Akt-TSC2-mammalian target of rapamycin (mTOR)-S6 kinase 33,34 would be more effective therapeutically. Although initial results indicate that this is the case, note that the full repertoire of Ras-dependent signaling pathways activated in NF1-null peripheral nerve sheath tumors has not yet been defined.…”

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

“…Additionally, downstream mTORC1 signaling has been shown to be active in Nf1-and Pten-deficient cells (Podsypanina et al, 2001;Johannessen et al, 2008). Hyperactivation of mTORC1 have further been established for RCC cell lines and tumors as well as for various NET cell lines and animal models (Chan et al, 2010), and in B50% of hepatocellular carcinomas (Villanueva et al, 2008).…”