FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2991322671> ?p ?o ?g. }

• W2991322671 endingPage "B108" @default.
• W2991322671 startingPage "B108" @default.
• W2991322671 abstract "Abstract Aberrantly activated PI3K/mTOR signaling is frequently implicated as an oncogenic driver in human cancer. In response to nutrient and growth factor stimuli, mTOR complex 1 (mTORC1) regulates cell growth and cap-dependent protein translation through phosphorylation and activation of S6K, and through phosphorylation and inactivation of the translational repressor 4EBP1. While suppression of mTORC1 activity causes rapid dephosphorylation of its substrates S6K and 4EBP1, it has also been reported that the translational repressor 4EBP3 is transcriptionally induced during prolonged mTORC1 inhibition.1 We have designed a series of complete and selective bi-steric inhibitors of mTORC1 by covalently linking rapamycin, a selective yet incomplete mTORC1 inhibitor, with mTOR kinase active-site inhibitors. These compounds potently and durably suppress phosphorylation of S6K and 4EBP1, induce growth suppression and apoptosis in multiple cancer cell lines, and cause tumor growth inhibition in xenograft models. In the present study we evaluated the utility of 4EBP3 mRNA expression as a pharmacodynamic (PD) biomarker of mTORC1 inhibition by our bi-steric inhibitors. We further interrogated whether tumor mTORC1 inhibition and anti-tumor efficacy could be predicted by monitoring this PD marker in surrogate tissue. First, we demonstrated that 4EBP3 mRNA and protein levels increased in response to mTORC1 inhibition in a concentration- and time-dependent manner in MDA-MB-468, MCF-7, and HCC1954 breast carcinoma cells. Kinetic studies in which we compared the response of bi-steric inhibitors to that of short duration-of-action active-site inhibitors revealed that 4EBP3 induction requires sustained mTORC1 inhibition, as loss of mTORC1 inhibition correlated with a rapid return to baseline 4EBP3 expression. Treatment with inhibitors of varying potency against mTORC1 also demonstrated a strong correlation between magnitude of cell growth inhibition and 4EBP3 mRNA induction. Additionally, suppression of tumor 4EBP1 phosphorylation and induction of 4EBP3 mRNA was observed in MCF-7 and HCC9154 tumor xenografts following in vivo administration of bi-steric inhibitors with a concomitant induction of murine 4ebp3 in peripheral blood mononuclear cells (PBMCs). Initial studies indicate that ex vivo exposure of human PBMCs to a mTORC1 inhibitor also promotes 4EBP3 mRNA expression. Together, these data suggest that 4EBP3 could provide a sensitive mRNA-based in vivo biomarker of prolonged mTORC1 inhibition, as is the case following administration of a single dose of a bi-steric mTORC1 inhibitor. The concordance between the responses in tumor and PBMC suggests it may be possible to monitor tumor mTORC1 inhibition by monitoring 4EBP3 in surrogate tissue. In summary, 4EBP3 mRNA represents a potential PD biomarker of mTORC1 inhibitor response as an alternative to measurement of the phosphorylation status of mTORC1 substrates. 1. Tsukumo, T., et al. Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3. Nat Commun 7:11776. doi: 10.1038/ncomms11776 (2016). Citation Format: Bianca J. Lee, Nuntana Dinglasan, Tram Nguyen, Ed Lorenzana, Stacy Wilson, G. Leslie Burnett, James B. Aggen, Robert J. Nichols, Mallika Singh, David Wildes, Jaqueline A.M. Smith. 4EBP3 mRNA as a biomarker of therapeutic response to treatment with mTORC1 inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B108. doi:10.1158/1535-7163.TARG-19-B108" @default.
• W2991322671 created "2019-12-05" @default.
• W2991322671 creator A5006843660 @default.
• W2991322671 creator A5018907119 @default.
• W2991322671 creator A5038156337 @default.
• W2991322671 creator A5041466378 @default.
• W2991322671 creator A5042229593 @default.
• W2991322671 creator A5057362852 @default.
• W2991322671 creator A5059056080 @default.
• W2991322671 creator A5062983432 @default.
• W2991322671 creator A5071968723 @default.
• W2991322671 creator A5086613983 @default.
• W2991322671 creator A5090760997 @default.
• W2991322671 date "2019-12-01" @default.
• W2991322671 modified "2023-09-27" @default.
• W2991322671 title "Abstract B108: <i>4EBP3</i> mRNA as a biomarker of therapeutic response to treatment with mTORC1 inhibitors" @default.
• W2991322671 doi "https://doi.org/10.1158/1535-7163.targ-19-b108" @default.
• W2991322671 hasPublicationYear "2019" @default.
• W2991322671 type Work @default.
• W2991322671 sameAs 2991322671 @default.
• W2991322671 citedByCount "1" @default.
• W2991322671 countsByYear W29913226712022 @default.
• W2991322671 crossrefType "journal-article" @default.
• W2991322671 hasAuthorship W2991322671A5006843660 @default.
• W2991322671 hasAuthorship W2991322671A5018907119 @default.
• W2991322671 hasAuthorship W2991322671A5038156337 @default.
• W2991322671 hasAuthorship W2991322671A5041466378 @default.
• W2991322671 hasAuthorship W2991322671A5042229593 @default.
• W2991322671 hasAuthorship W2991322671A5057362852 @default.
• W2991322671 hasAuthorship W2991322671A5059056080 @default.
• W2991322671 hasAuthorship W2991322671A5062983432 @default.
• W2991322671 hasAuthorship W2991322671A5071968723 @default.
• W2991322671 hasAuthorship W2991322671A5086613983 @default.
• W2991322671 hasAuthorship W2991322671A5090760997 @default.
• W2991322671 hasConcept C104202773 @default.
• W2991322671 hasConcept C104317684 @default.
• W2991322671 hasConcept C11960822 @default.
• W2991322671 hasConcept C150194340 @default.
• W2991322671 hasConcept C158448853 @default.
• W2991322671 hasConcept C184235292 @default.
• W2991322671 hasConcept C185592680 @default.
• W2991322671 hasConcept C2777949483 @default.
• W2991322671 hasConcept C502942594 @default.
• W2991322671 hasConcept C55493867 @default.
• W2991322671 hasConcept C62478195 @default.
• W2991322671 hasConcept C86554907 @default.
• W2991322671 hasConcept C86803240 @default.
• W2991322671 hasConcept C95444343 @default.
• W2991322671 hasConcept C98490376 @default.
• W2991322671 hasConceptScore W2991322671C104202773 @default.
• W2991322671 hasConceptScore W2991322671C104317684 @default.
• W2991322671 hasConceptScore W2991322671C11960822 @default.
• W2991322671 hasConceptScore W2991322671C150194340 @default.
• W2991322671 hasConceptScore W2991322671C158448853 @default.
• W2991322671 hasConceptScore W2991322671C184235292 @default.
• W2991322671 hasConceptScore W2991322671C185592680 @default.
• W2991322671 hasConceptScore W2991322671C2777949483 @default.
• W2991322671 hasConceptScore W2991322671C502942594 @default.
• W2991322671 hasConceptScore W2991322671C55493867 @default.
• W2991322671 hasConceptScore W2991322671C62478195 @default.
• W2991322671 hasConceptScore W2991322671C86554907 @default.
• W2991322671 hasConceptScore W2991322671C86803240 @default.
• W2991322671 hasConceptScore W2991322671C95444343 @default.
• W2991322671 hasConceptScore W2991322671C98490376 @default.
• W2991322671 hasIssue "12_Supplement" @default.
• W2991322671 hasLocation W29913226711 @default.
• W2991322671 hasOpenAccess W2991322671 @default.
• W2991322671 hasPrimaryLocation W29913226711 @default.
• W2991322671 hasRelatedWork W1971357899 @default.
• W2991322671 hasRelatedWork W1995496043 @default.
• W2991322671 hasRelatedWork W2007655533 @default.
• W2991322671 hasRelatedWork W2021510881 @default.
• W2991322671 hasRelatedWork W2038098576 @default.
• W2991322671 hasRelatedWork W2073104926 @default.
• W2991322671 hasRelatedWork W2080391155 @default.
• W2991322671 hasRelatedWork W2253279387 @default.
• W2991322671 hasRelatedWork W2499779639 @default.
• W2991322671 hasRelatedWork W2919866161 @default.
• W2991322671 hasVolume "18" @default.
• W2991322671 isParatext "false" @default.
• W2991322671 isRetracted "false" @default.
• W2991322671 magId "2991322671" @default.
• W2991322671 workType "article" @default.