Bi-steric mTORC1 inhibitors induce apoptotic cell death in tumor models with hyperactivated mTORC1
The PI3K-AKT-mTOR pathway is commonly dysregulated in cancer. Rapalogs exhibit modest clinical benefit likely due to their lack of effects on 4E-BP1. We hypothesized that bi-steric mTORC1-selective inhibitors would have greater potential for clinical benefit than rapalogs in tumors with mTORC1 dysfunction.  We assessed this hypothesis in tumor models with high mTORC1 activity both in vitro and in vivo.  Bi-steric inhibitors had strong growth inhibition, eliminated phosphorylated 4EBP1, and induced more apoptosis than rapamycin or MLN0128. Multi-omic analysis showed extensive effects of the bi-steric inhibitors in comparison to rapamycin. De novo purine synthesis was markedly and selectively inhibited by bi-sterics through reduction in JUN and its downstream target PRPS1 and appeared to be the cause of apoptosis. Hence, bi-steric mTORC1-selective inhibitors are a novel therapeutic strategy to treat tumors driven by mTORC1 hyperactivation. Overall design: To gain a detailed view of how bi-steric mTORC1-selective inhibition contrasted with the effects of rapamycin, RNA-seq was performed on two representative cell lines (HCV29 TSC1-null and 705 Tsc2-null) treated with RMC-6272 (3 nM, 24h), rapamycin (10 nM, 24h), or DMSO as the negative control.