Targeting mTOR with rapamycin: one dose does not fit all

Abstract

A puzzling aspect of rapamycin-based therapeutic strategies is the wide disparity in the doses needed to suppress mTOR under different circumstances. A recent study revealing mechanistically how rapamycin suppresses mTOR provides two explanations for the differential sensitivities to rapamycin. First, mTOR exists as two functionally distinct complexes (mTORC1 and mTORC2), and while rapamycin suppresses both, it does so at very different concentrations. Whereas mTORC1 is suppressed by concentrations of rapamycin in the low nM range, mTORC2 generally requires low muM concentrations. Second, the efficacy of rapamycin is dependent on the level of phosphatidic acid (PA), which is required for the assembly of both mTORC1 and mTORC2 complexes. Rapamycin interacts with mTOR in a manner that is competitive with PA. Therefore, elevated levels of PA, which is common in cancer cells, increases the level of rapamycin needed to suppress both mTORC1 and mTORC2. A practical outcome of the recent study is that if PA levels are suppressed, mTORC2 becomes sensitive to concentrations of rapamycin that can be achieved clinically. Since mTORC2 is likely more critical for survival signals in cancer cells, the recent findings suggest new strategies for enhancing the efficacy of rapamycin-based therapeutic approaches in cancer cells.

Figure 1

Model for the differential effects of rapamycin on mTORC1 and mTORC2. The stability of mTORC2 is much stronger than mTORC1, and therefore, there are fewer dissociations of mTORC2 to PA, Rictor and free mTOR. And it is the free mTOR that binds rapamycin-FKBP12. The ability of rapamycin-FKBP12 to suppress mTORC1 and mTORC2 would be dependent on the frequency that free mTOR becomes available to bind rapamycin-FKBP12. There would be far more dissociated mTOR generated from mTORC1 than from mTORC2 and therefore less rapamycin would be required to compete with PA for binding to the mTOR derived from mTORC1. In contrast, the rare dissociations of mTORC2 would require much more rapamycin-FKBP12 to compete with PA to capture the rare mTOR proteins derived from mTORC2. Reducing PA levels by suppressing the hydrolysis of phosphatidylcholine (PC) to PA shifts the equilibrium in favor of dissociation of the mTORC2 complex and therefore reduces the concentration of rapamycin-FKBP12 needed to bind to and suppress mTORC2. The larger arrows reflect relative differences in the direction for the equilibrium between free mTOR and the mTOR complexes. This model is clearly an over-simplification in that there are other components of the mTOR complexes that are not considered such as mSin1 and Protor that are part of mTORC2, and which could contribute to the greater stability of mTORC2.