Abstract #5647: Enhancing mTORi efficacy by decreasing AKT feedback loop with arsenic trioxide

Several novel rapamycin-derivatives have entered into clinical trials as inhibitors of the mammalian target of rapamycin (mTOR). These inhibitors (mTORi) have exciting clinical activity in renal cell carcinoma, breast cancer, and some hematologic malignancies. However, there is growing evidence that the potential benefits of mTOR inhibition are limited by a feedback mechanism that results in AKT activation. While mTORi can block important growth promoting events downstream from TORC1, an increased activation of AKT may inhibit apoptotic signals. It has been postulated that the increased AKT activity resulting from mTOR inhibition is a result of increased IGF signaling or alternatively, via the second mTOR complex, TORC2, which may not be inhibited by the mTORi tested to date. We have previously shown that arsenic trioxide (ATO) inhibits AKT activity and in some cases, decreases AKT protein expression. Therefore, we propose that combining ATO and mTORi may circumvent the AKT feedback loop and increase the anti-tumor effects of these drugs. Using a panel of breast cancer cell lines, we find that ATO, at clinically achievable doses, can enhance the inhibitory activity of the mTORi temsirolimus in some, but not all, cell lines. MCF-7, MDA-MB-468, and SKBR3, but not T47D cells, exhibit a decrease in cell number that correlates with an increase in the percentage of cells arrested in the G0/G1 phase of the cell cycle. In all these cell lines, temsirolimus treatment resulted in AKT activation, which was decreased by concomitant ATO treatment only in MCF-7, MDA-MB-468, and SKBR3 cell lines. Recent studies show that mTORi treatment also results in activated ERK signaling, a finding we confirmed in our cell lines. ATO co-treatment decreased ERK activation, as well as total ERK protein expression, in MCF7 and SKBR3. Therefore, we propose that adding ATO to mTORi treatment may overcome the negative feedback loop by decreasing MAPK and activated AKT in addition, to the downstream targets of mTOR/TORC1. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5647.