Loss-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.
Tumor suppressors are often mutated in human cancer; however, the excessive proteasomal destruction of tumor suppressor proteins also promotes tumorigenesis. Here we show that the NF1 protein is destabilized in sporadic GBMs as a consequence of the hyperactivation of PKC. Notably, this destabilization confers sensitivity to PKC inhibitors. In contrast, a separate subset of GBMs that possess NF1 mutations are insensitive to PKC inhibitors but are sensitive to mTOR inhibitors. These findings reveal a broad role for NF1-inactivation in gliomagenesis and illustrate how different mechanisms of inactivation are utilized in the same tumor-type. Moreover they highlight the importance of elucidating the molecular mechanisms that underlie tumorigenesis, as such knowledge may be essential for developing personalized therapies.