interruption of single nodes within the PI3K network can suppress this negative feedback auto regulation and endow tumor cells with compensatory molecular signals that counteract drug action. Moreover, the prior experience with other molecule targeted drugs strongly suggest that, even in patients who initially respond to these drugs, single agent PI3K ATP-competitive HSP90 inhibitor inhibitors will be insufficient to cure patients with advanced disease. The existence of a TORC1 PI3K/Akt negative feedback loop has been well documented in studies with cells in culture. Recently, however, two clinical studies elegantly documented that pharmacological inhibition of TORC1 led to Akt activation as measured by tumor levels of Ser473 P Akt in patients with breast cancer and glioblastoma.

These findings have important therapeutic implications carcinoid syndrome as they imply that the limited efficacy of TORC1inhibitors might be due to their intrinsic capacity to abrogate this negative feedback to Akt. Indeed, in the study by OReilly et al., inhibition of TORC1 with everolimus led to insulin like growth factor I receptor/IRS 1 dependent activation of Akt. IGF IR inhibition with small molecule TKIs prevented RAD001 induced Akt phosphorylation and sensitized tumor cells to the TORC1 inhibitor. Based, in part, on these data, at this time, clinical trials testing combinations of mTOR inhibitors with neutralizing IGF IR monoclonal antibodies are in progress. In another relevant example, inhibition of TORC1 with rapalogs in primary breast tumors and in xenografts induced a dose dependent increase in MAPK activation which was dependent on an S6K PI3K RAS pathway.

Supporting the notion that this compensation limits the therapeutic inhibition of a single pathway, the combined inhibition of mTOR and MEK has shown synergistic activity against several cancer xenografts. Therefore, although PI3K inhibitors 2-ME2 molecular weight have not yet been shown to induce upregulation of MEK, it is not unreasonable to expect they will do so in cells where PI3K inhibitors downregulate TORC1 activity downstream. Based in part on these data, combinations of TORC1/TORC2 inhibitors with MEK inhibitors and Akt inhibitors with MEK inhibitors are under early planning. Furthermore, since activation of mTOR downregulates PDGF receptor signaling, it is likely that inhibition of mTOR will also lead to PDGFR activation in some cancers.

In tumors where this receptor is overexpressed, this response would limit the action of mTOR inhibitors and potentially inform the use of novel therapeutic combinations aimed at blocking such compensatory response. Two papers have recently shown that inhibition of MEK with a small molecule inhibitor, although partially effective, leads to feedback upregulation of PI3K/Akt in human breast cancer cells with a basal like gene expression signature. This compensatory response upon therapeutic inhibition of MEK was enhanced in cells lacking PTEN.