We all know how tetchy we can be after skipping that vital cup of morning coffee; well, cancer cells can become addicted to stimulants, too. Two papers in the August 28 issue of Proceedings of the National Academy of Sciences reveal that cancer cells with a hyperactive phosphatidylinositol 3-kinase (PI3K) pathway become reliant on it to activate FRAP1 (mTOR), a kinase that regulates ribosome biogenesis. This makes these cells more sensitive to rapamycin — a drug that is already on the market as an immunosuppressant.

The PI3K pathway is frequently activated in cancer cells: amplification of PI3K itself causes the overproduction of 3-phosphorylated inositol lipids, which activate a protein kinase called AKT. The same effect can be achieved by loss of PTEN, the phosphatase that removes the 3-phosphate from inositol lipids, thereby inactivating them as second messengers. An obvious way to block this pathway would be to inhibit AKT, but no AKT-selective inhibitors have yet been developed.

FRAP1 is phosphorylated and activated by AKT, although it can also be activated independently of AKT. Might blocking FRAP1 inhibit the growth of cells that are overdoing the 3-phosphorylated inositol lipids? Charles Sawyers and colleagues investigated this possibility in Pten+/+ and Pten−/− mouse embryonic fibroblasts, and in a panel of human cancer cell lines with known PTEN status, using CCI-779 — an esterified form of rapamycin. Nanomolar concentrations of CCI-779 blocked proliferation (determined by 3H-thymidine uptake) in all the PTEN−/− cells. But is this due to FRAP1 inhibition? The activity of S6 kinase, a downstream target of FRAP1, was upregulated in PTEN−/− cells by both increased protein production and inceased phosphorylation, but treatment with CCI-779 reduced S6 kinase to undetectable levels.

What effect does CCI-779 have in vivo? Tumour growth was inhibited in both PTEN+/+ and PTEN−/− tumours that were grown in immunodeficient mice, but the PTEN−/− tumours were much more sensitive to the drug. This was due to FRAP1 inhibition because phosphorylation of S6 kinase, which was increased in PTEN−/− tumour explants from untreated animals compared with PTEN+/+ explants, was almost undetectable in CCI-779-treated animals. CCI-779 reduced tumour volume by decreasing cell division and reducing cell size, but it didn't stimulate apoptosis.

Analysis of two downstream targets of FRAP1, S6 kinase and 4E-BP1, showed that CCI-779 blocked FRAP1 signalling regardless of PTEN status, so one explantion for why PTEN−/− cells are more sensitive to the drug than PTEN+/+ cells is that they've become 'hooked' on PI3K signalling to activate cell division, even though there are other pathways that can do the job.

In the second paper, Ramon Parsons and colleagues describe the effects of CCI-779 in Pten+/− mice, which develop endometrial cancers and phaeochromocytomas that frequently show loss of heterozygosity of the second Pten allele. Treatment of Pten+/− mice with CCI-779 for 20 weeks significantly reduced tumour volume and, again, this seemed to be due to growth inhibition rather than cell killing.

So, by preventing PTEN−/− cancers — which include prostate and endometrial tumours and glioblastomas — from activating FRAP1 through the PI3K pathway, we might be able to halt their growth. AKT remains an enticing therapeutic target as its inhibition should block PI3K-mediated growth and survival signals. But, in the meantime, CCI-779 is worthy of clinical investigation.