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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 Article has an altmetric score of 2

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

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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 6

Bi-steric compounds showed more dramatic tumor suppression and less tumor regrowth in the Tsc2+/– A/J mouse kidney cancer model.

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Bi-steric compounds showed more dramatic tumor suppression and less tumo...
(A) Schematic diagram of treatment strategy. (B) Tumor volume from semiquantitative analysis of H&E slides immediately after treatment or 2 months after treatment. Dots are individual values (n = 6); a median line is shown. One-way ANOVA was used. *P < 0.05, **P < 0.01, ***P < 0.001. (C) Toxicity evaluation of compounds as judged by body weight. Each dot represents median (n = 6). (D and E) Images of whole mouse kidneys (D) and H&E-stained kidney sections (E) after 4 weeks of treatment and another 2-month tumor regrowth from mice as in A, both immediately after treatment and after 2-month regrowth. Scale bar: Mm ruler (D) and 5 mm (E). (F) H&E and IHC staining of kidney sections after 4 weeks of treatment and after 2 months of tumor regrowth. Scale bar: 30 μm.

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