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A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors [I]

ABSTRACT: A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors [I]

PROVIDER: PRJNA722519 | ENA |

REPOSITORIES: ENA

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A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors [II]

Project description:mTOR is a serine/threonine kinase with a crucial role in regulating fundamental cellular processes and is an attractive anticancer target. Multiple clinical trials of mTOR kinase inhibitors such as AZD2014 that suppress both mTORC1 and mTORC2 are ongoing, but their specificity and toxicity features remain a concern. We have developed an inducible kinase-dead D2338A mTOR mouse knock-in model and show that it is useful to study the kinase-independent function of mTOR and for assessing the off-target effects of mTOR kinase inhibitors. We found that while the mTOR KI mice in hematopoietic system displayed similar phenotypes to that of mTOR KO mice, they have significantly prolonged survival time than the KO mice. Whereas AZD2014 was mostly on-target in suppressing mTOR kinase activity, mimicking that seen in KI stem cells in transcriptome analysis, off-target genes in KI cells induced by AZD2014 including Ahnak2, Emp1, Lilrb4, Tpsb2, and Cma1 were detected. Our studies reveal kinase-independent function of mTOR in hematopoiesis and presents a mouse model for precisely assessing specificity of mTOR kinase inhibitors. Stringent test of drugs with such mouse models in the preclinical setting may provide useful information guiding the safety and efficacy of related clinical trials.

2023-08-29 | GSE172248 | GEO

A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors [I]

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A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors [III]

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A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors

Project description:A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors

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A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors [II]

Project description:A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors [II]

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A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors [III]

Project description:A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors [III]

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Tumor-independent host gene expression changes induced by tyrosine kinase inhibitors

Project description:Transcriptome analysis was used to identify tumor-independent changes after treatment with different tyrosine kinase inhibitors (TKIs).

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Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes so there is great interest in understanding mTOR regulatory networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin only inhibits a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. To examine the complete spectrum of mTOR responsive cellular processes, we compared the transcriptional profiles of mammalian cells treated with rapamycin versus the ATP-competitive inhibitor PP242. Our analysis provides a genome-wide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin. Gene expression in mouse NIH3T3 cells was measured after 18 hour treatment with DMSO (control), 50 nM rapamycin, or 2 uM PP242. Four independent experiments were performed for each condition.

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