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 4

Bi-steric compounds showed greater tumor suppression in vivo than rapamycin.

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Bi-steric compounds showed greater tumor suppression in vivo than rapamy...
(A) Tumor volume of human BLCA PDX-2211 treated for 4 weeks followed by 2-month treatment cessation. Each dot and error bar represent mean ± SD (n = 8 mice per group, 2 tumors per mouse). Rapamycin: 3 mg/kg, 3 times/wk. MLN0128: 0.75 mg/kg, 5 times/wk. RMC-6272: 8 mg/kg, once per week. Student’s t test was used. **P < 0.01, ****P < 0.0001. (B) Waterfall plot showing the response of tumors in different treatment groups after 4-week treatment (as in A). Each bar represents a mouse with 2 tumors (n = 8 mice per group). (C and D) Purine metabolites are those most decreased by global metabolite analysis of a human BLCA PDX after 24 hours of treatment with RMC-6272 (8 mg/kg) compared with rapamycin (3 mg/kg). Dots are individual values (n=3); a median line is shown. One-way ANOVA was used. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. (E) H&E and IHC staining of BLCA PDX dosed once (same dose as in A) followed by washout for 4, 24, 72, and 168 hours as indicated at the top. Scale bar: 30 μm. c-PARP, cleaved PARP; CC3, cleaved caspase 3.