Bi-steric mTORC1 inhibitors induce apoptotic cell death in tumor models with hyperactivated mTORC1
Heng Du, … , Mallika Singh, David J. Kwiatkowski
Heng Du, … , Mallika Singh, David J. Kwiatkowski
Published November 1, 2023
Citation Information: J Clin Invest. 2023;133(21):e167861. https://doi.org/10.1172/JCI167861.
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Research Article Oncology

Bi-steric mTORC1 inhibitors induce apoptotic cell death in tumor models with hyperactivated mTORC1

Abstract

The PI3K/AKT/mTOR pathway is commonly dysregulated in cancer. Rapalogs exhibit modest clinical benefit, likely owing to their lack of effects on 4EBP1. 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. Multiomics analysis showed extensive effects of the bi-steric inhibitors in comparison with rapamycin. De novo purine synthesis was 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 therapeutic strategy to treat tumors driven by mTORC1 hyperactivation.

Authors

Heng Du, Yu Chi Yang, Heng-Jia Liu, Min Yuan, John M. Asara, Kwok-Kin Wong, Elizabeth P. Henske, Mallika Singh, David J. Kwiatkowski

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Figure 2

Multiomics analysis of effects of RMC-6272 versus rapamycin.

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Multiomics analysis of effects of RMC-6272 versus rapamycin. (A) Gene se...
(A) Gene set enrichment analysis (GSEA) of RNA data comparing RMC-6272– and rapamycin-treated TSC1-null HCV29 cells. The most downregulated pathways after RMC-6272 treatment are shown. (B) Seventy-three cell cycle genes were decreased in mRNA expression (FPKM) in RMC-6272–treated HCV29 cells compared with DMSO- or rapamycin-treated cells. (C) Purine metabolism was the metabolic pathway showing the most significant decrease in metabolite levels following RMC-6272 compared with rapamycin treatment in HCV29 TSC1-null cells, by MSEA. (D and E) Lipid map indicating lipid changes comparing RMC-6272– with rapamycin-treated HCV29 TSC1-null cells. Green nodes correspond to active lipids and arrows to conversion pathways. Z scores were used to assess significance. Reactions with a positive z score have green arrows, while negative z scores are colored purple. (F) Global proteomics analysis of RMC-6272– versus rapamycin-treated HCV29 TSC1-null cells led to identification of proteins involved in protein localization, targeting, and folding as being most downregulated with RMC-6272 treatment compared with rapamycin. (G) Global phosphoproteomics analysis of RMC-6272– versus rapamycin-treated 705 Tsc2-null cells identified ribonucleoprotein biogenesis and RNA splicing pathways enriched for phosphoproteins that were downregulated with RMC-6272 treatment compared with rapamycin using GSEA.