Bi-steric mTORC1-selective Inhibitors activate 4EBP1 reversing MYC-induced tumorigenesis and synergize with immunotherapy
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ABSTRACT:
PROVIDER: PRJNA814212 | ENA |
REPOSITORIES: ENA
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Project description:We evaluated the therapeutic efficacy and transcriptome changes induced in hepatocellular carcinoma upon treatment of Lap-tTA/Tet-O-MYC transgenic mice with two Bi-steric mTORC1-selective inhibitors, sorafenib, or doxycycline to inactivate MYC via the TET system at different time points post treatment.
2025-09-09 | GSE198201 | GEO
Project description: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.
2023-11-08 | GSE236742 | GEO
Project description:The clinical benefit of current mTOR inhibitors is limited, perhaps reflecting their intrinsic pharmacological profiles. Rapamycin analogs selectively inhibit mTORC1, but fail to suppress phosphorylation of the mTORC1 substrate 4EBP1, a translational repressor that is a key driver of oncogenic mTORC1 signaling. mTOR kinase active-site inhibitors fully suppress mTORC1 and phosphorylation of its substrates, but are active against mTORC2 and additional kinases, potentially contributing to tolerability limitations. The prototype bi-steric inhibitor RapaLink-1 exploits the selective mTORC1 interactions of rapamycin and the broad mTOR kinase inhibitory effects of an active-site inhibitor, through covalent linkage of the two pharmacophores to achieve complete mTORC1/2 inhibition. We demonstrate that the anti-proliferative activity of RapaLink-1 is dependent upon mTORC1 and suppression of 4EBP1 phosphorylation. Using a rational design strategy, we tuned the affinities of the rapamycin core and ATP-mimetic moieties to create novel bi-steric inhibitors with enhanced mTORC1 selectivity and potency against 4EBP1 phosphorylation. mTORC1-selective bi-steric compounds produced durable inhibition of 4EBP1 phosphorylation in vitro and in vivo, and drove tumor regressions at well-tolerated doses in xenograft models of breast cancer.
2021-04-05 | GSE138417 | GEO
Project description:Activation of the PI3K-mTOR pathway is central to breast cancer pathogenesis including resistance to many targeted therapies. The mTOR kinase forms two distinct complexes, mTORC1 and mTORC2, and understanding which is required for the survival of malignant cells has been limited by tools to selectively and completely impair either subcomplex. To address this, we used RMC-6272, a bi-steric molecule with a rapamycin-like moiety linked to an mTOR active-site inhibitor that displays >25-fold selectivity for mTORC1 over mTORC2 substrates. Complete suppression of mTORC1 by RMC-6272 causes apoptosis in ER+/HER2- breast cancer cell lines, particularly in those that harbor mutations in PIK3CA or PTEN, due to inhibition of the rapamycin resistant, mTORC1 substrate 4EBP1 and reduction of the pro-survival protein MCL1. RMC-6272 reduced translation of ribosomal mRNAs, MYC target genes, and components of the CDK4/6 pathway, suggesting enhanced impairment of oncogenic pathways compared to the partial mTORC1 inhibitor everolimus. RMC-6272 maintained efficacy in hormone therapy-resistant acquired cell lines and patient derived xenografts (PDX), showed increased efficacy in CDK4/6 inhibitor treated acquired resistant cell lines versus their parental counterparts, and was efficacious in a PDX from a patient experiencing resistance to CDK4/6 inhibition. Bi-steric mTORC1-selective inhibition may be effective in overcoming multiple forms of therapy-resistance in ER+ breast cancers.
2024-06-01 | GSE230627 | GEO
Project description:A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer
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Project description:The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown. Surprisingly, 4EBP1 is a target of genomic copy number gains (Chr. 8p11) in breast and lung cancer. We notice that 4EBP1 gains are genetically linked to gains in neighboring genes including WHSC1L1 and FGFR1. Our results show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites. This implies that not 4EBP1 but instead FGFR1 is the genetic target of Chr. 8p11 gains in breast and lung cancer. Accordingly, these tumors show increased sensitivity to FGFR1 and PI3K inhibition and this is a therapeutic vulnerability through restoring the tumor-suppressive function of 4EBP1. Ribosome profiling reveals genes involved in insulin signaling, glucose metabolism, and inositol pathway to be the relevant translational targets of 4EBP1. These mRNAs are among the top 200 translation targets and are highly enriched for structure and sequence motifs in their 5’UTR that depends on the 4EBP1-EIF4E activity. In summary, we identify the translational targets of 4EBP1-EIF4E that facilitate the tumor suppressor function of 4EBP1 in cancer.
2022-03-05 | GSE197735 | GEO
Project description:We investigated the function of the mTORC1 substrates and mRNA translation regulators 4EBP1/2 in the response to glucose deprivation. We uncovered that targeting 4EBP1/2 expression had a direct impact on the survival rates of cells challenged with glucose deprivation. To further define the mechanisms underlying 4EBP1/2 function under glucose deprivation, we conducted a proteomics analysis of HEK293 shRNA control and HEK293 shRNA 4EBP1/2 grown in basal media or under glucose deprivation (1 mM glucose containing media) for 30 hours.
2024-03-28 | PXD040931 | Pride
Project description:To investigate the changes in gene expression upon loss of 4EBP1/2, we performed RNA-seq and differential gene expression analysis on WT and derived 4EBP1/2 KD cell lines. The canonical and 5′TOP mRNA cell lines used for single-molecule imaging were treated as biological replicates for the differential gene expression analysis.
2024-01-15 | GSE233182 | GEO
Project description:Histone monoaminylation is a new class of chromatin post-translational modification whereby glutamines are transamidated by tissue transglutaminase 2 (TGM2). Initial studies of these marks have identified serotonylation and dopaminylation on H3Q5, suggesting the modification is a marker of active chromatin. However, little work has been conducted to understand the regulation of TGM2-mediated monoaminylation of chromatin. Here, we employed a highly sensitive TGM2 assay using the small molecule biotin-cadaverine as an acyl-acceptor substrate. In doing so, we discovered that, in addition to H3Q5, H3Q19 and H2A.ZQ123 and Q124 are glutaminyl substrates for TGM2 in vitro. Modification of these residues occurs in a sequence independent manner, with the primary determining factor for substrate selectivity being steric accessibility. We demonstrated that moving substrate glutamines near the histone fold domain turns them into non-substrates. Furthermore, we found that steric accessibility of glutamines appears to be controlled by higher order chromatin structures. Using nucleosome arrays as substrates, we successfully showed that formation of chromatin fibers in vitro reduces levels of monoaminylation. We then successfully extended these findings to a cell based system, showing that TGM2 is not enriched in heterochromatin and that H3Q5 serotonylation and H3K9me3 are mutually exclusive marks. In total, our results strongly suggest that TGM2, and monoaminylation, are excluded from heterochromatin based on steric accessibility
2022-10-05 | GSE198978 | GEO