Figure 2

Potential tumor-specific differences in therapeutic end points. Although inhibition of PI3K/Akt/mTOR signaling is a feasible approach in both glioblastoma and neuroblastoma, the molecular background of those two malignancies is very different. While glioblastoma exhibits amplification of HER1/EGFR with coexpression of the activated EGFRvIII variant [53], their main feature with regards to the PI3K signaling network is the frequent inactivation of PTEN [11]. In contrast, neuroblastoma does not exhibit any frequent mutation within the PI3K/Akt/mTOR signaling cascade, but often displays overexpression of several receptor tyrosine kinases [42, 43]. Interestingly, our own data suggest that the downstream effectors that need to be inhibited to chemosensitize these tumors to chemotherapy are different. Glioblastoma is sensitized for doxorubicin-induced apoptosis via blocking DNA-PK activation, i.e. DNA repair [24], while in neuroblastoma this seems to be mediated at the level of mitochondria via VDAC1 [5]. It remains to be seen whether this is an isolated phenomenon, due to low numbers of cell lines investigated, or whether different arms of the PI3K network have a different weighting dependent on the malignancy.