Prediction and Optimization of the Therapeutic Effect of mTOR Inhibitors in Aggressive B-Cell Lymphomas

Mechanistic target of rapamycin complex 1 (mTORC1) is a central integrator of nutrient and growth factor inputs that controls cell growth in all eukaryotes. Rapamycin and its analogs (rapalogs) have been approved for the treatment of relapsed mantle cell lymphoma. A large proportion of aggressive B-cell lymphoma patients, however, respond poorly to rapalogs. The second generation of mTOR inhibitors function as ATP-competitive inhibitors (TORi), directly targeting the mTOR catalytic site. TORis have been proven to be more effective than rapalogs in cancer treatment. However, the mechanism underlying the cytotoxic effect of TORis in aggressive B-cell lymphomas remains unclear. In this study, we demonstrated that TORi-induced apoptosis is predominantly dependent on loss of mTORC1-mediated 4EBP phosphorylation. Knocking out Rictor, a key component of mTORC2, or inhibiting p70S6K has little effect on TORi-induced apoptosis. In contrast, increasing the EIF4E:4EBP ratio by either overexpressing EIF4E or knocking out 4EBP1/2 protected lymphoma cells from TORi-induced cytotoxicity. Furthermore, down-regulation of MCL1 and BCL-XL expression plays an important role in TORi-induced apoptosis whereas BCL-2, in cells with high expression, confers resistance to TORi treatment. Based on the mechanism study, we demonstrated that BH3 profiling, primarily NOXA and HRK stimulation, can effectively predict the cytotoxicity of the TORi in lymphoma cells. Also, in combination with pro-apoptotic drugs, especially BCL-2 inhibitors, the TORi exerted powerful anti-tumor effects both in vitro and in vivo. Taken together, this study provides mechanistic insight in TORi treatment in aggressive B-cell lymphoma and identified a mean to predict and improve its effectiveness clinically.