Clinical and translational data suggest that sensitive tumor types, with adequate parameters and functional apoptosis pathways, might not need high doses of mTOR inhibitors to trigger apoptosis. In most cases, cancer cells might only be partially sensitive to mTOR inhibitors due to redundant signal transduction or lack of functional apoptosis signaling pathways. In situations like this, high doses of mTOR inhibitors might be required. In a recent study of patients with Renal cell carcinoma, resistance to Temsirolimus was associated with low levels of p-AKT and p-S6K1, that play the key role in mTOR activation. These data strongly suggests number of tumors with an activated PI3K/AKT/mTOR signaling pathway that does not respond to mTOR inhibitors. For future studies, it is recommended to exclude patients with low or negative p-AKT levels from trials with mTOR inhibitors.
Current data is insufficient to predict sensitivity of tumors to rapamycin. However, the existing data allows us to characterize tumors that might not respond to rapalogs.