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.
