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Development of a SIN1 targeting inhibitor as a novel therapeutic approach for the treatment of malignancies

ABSTRACT: We have developed a novel mTOR pathway inhibitor via targeting SIN1. We used multiple proteomics analyses to determine mechanism of action of our novel Sin1 inhibitor and compare to other mTOR pathway inhibitors.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukemia Cell

DISEASE(S): Leukemia

SUBMITTER: Michael Caldwell

LAB HEAD: Leonidas Platanias

PROVIDER: PXD040955 | Pride | 2026-01-26

REPOSITORIES: Pride

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			Action	DRS
	20210624_vcs075_21-2603_Platanias_Beauchamp_1-RIC-ctl.mgf	Mgf
	20210624_vcs075_21-2603_Platanias_Beauchamp_1-RIC-ctl.raw	Raw
	20210624_vcs075_21-2603_Platanias_Beauchamp_2-RIC-760.mgf	Mgf
	20210624_vcs075_21-2603_Platanias_Beauchamp_2-RIC-760.raw	Raw
	20210624_vcs075_21-2603_Platanias_Beauchamp_3-SIN1-ctl.mgf	Mgf

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Development of a SIN1 targeting inhibitor as a novel therapeutic approach for the treatment of malignancies

Project description:We have developed a novel mTOR pathway inhibitor via targeting SIN1. We used multiple proteomics analyses to determine mechanism of action of our novel Sin1 inhibitor and compare to other mTOR pathway inhibitors.

2026-01-26 | PXD040950 | Pride

Development of a SIN1 targeting inhibitor as a novel therapeutic approach for the treatment of malignancies

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Changes in global gene expression in SIN1 knock-out murine epithelial fibroblasts

Project description:RNA from wt and SIN1 knock-out MEF cell lines were compared Using affymetrix murine gene chip, the effects of SIN1 ablation on global gene transcription were assessed

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Sin1-mTORC2 Augments Lipid Anabolism of Tumor-associated Macrophages to Limit the Type I Interferon-dependent Anti-tumor Immunity

Project description:The biological consequences and mechanisms of metabolic reprogramming of macrophages in the tumor microenvironment (TME) remain largely elusive. Here we showed, in part by myeloid-specific ablation of Sin1, a key component of mammalian target of rapamycin complex (mTORC) 2, that the Sin1-mTORC2-Akt-sterol regulatory element-binding proteins (SREBPs) signaling was augmented in tumor-associated macrophages (TAMs), leading to excessive lipid synthesis and accumulation, which consequently impaired the STING-dependent type I interferon production and CD8+ T cell mediated anti-tumor immunity. The ability of Sin1 deficiency in TAMs to inhibit lipid synthesis and enhance anti-tumor immunity could be blunted by the accumulation of cholesterol/lipids in TAMs. Furthermore, genetic ablation of Sin1 in TAMs or pharmacologic inhibition of lipid anabolism acted synergistically with immune checkpoint blockade (ICB)-based cancer therapy to control tumor growth. Finally, elevated Sin1-mTORC2-Akt activity and lipid anabolism as well as decreased type I IFN responses were all observed in TAMs from human colon cancers and tightly associated with poor patient survival. Together, our study uncovers a novel role of Sin1-regulated lipid anabolic pathway in TAMs which acts as a metabolic checkpoint for anti-tumor immunity via limiting a STING-dependent type I IFN response.

2025-03-17 | GSE198880 | GEO

Expression data from U937 cells infected by hsa-miR-608 inhibitor virus

Project description:The expression level of miR-608 was found to be down regulated in several types of cancer. In our previous study, a single SNP in miR-608 (rs4919510) was found to be strongly associated with a higher risk of developing sepsis and multiple organ dysfunctions in all 3 independent study cohorts. However, the clinicopathological impact and the exact roles of miR-608 and its underlying molecular mechanisms in inflammation remain to be identified. In order to identify the exact terget gene of miR-608 in monocytes, we constructed lentiviral vectors with has-miR-608 inhibitor sequences and transfected U937 cells.We used microarrays to identified distinct classes of up-regulated genes during this process and look for possible target genes. U937 cells transfected by has-miR-608 inhibitor lentiviral vectors or negative control virus were analyzed. There are three samples in each group.

2015-12-12 | E-GEOD-75911 | biostudies-arrayexpress

Changes in global gene expression in SIN1 knock-out murine epithelial fibroblasts

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ABPP of Ibrutinib Resistance in B Cell Malignancies

Project description:Ibrutinib,a novel Bruton'styrosine kinase inhibitor, demonstrated high response rates in B-cell lymphomas but a growing number of ibrutinib treated patients relapse with resistance, fulminant progression and accelerated mortality. Using chemical proteomics and a high-throughput ex vivo assay in a reconstructed tumor microenvironment (TME), we determined the molecular basis for ibrutinib activity and mechanism of acquired ibrutinib resistance. Reciprocal activation of PI3K-AKT-mTOR and integrin β1 signaling were identified as a signaling hub of kinome for ibrutinib resistance, resulting in enforced TME-lymphoma interactions, promoting mantle cell lymphoma (MCL) growth and drug resistance. Combinatorial disruption of BCR signaling and ibrutinib resistance associated pathways led to release of MCL cells from TME, reversal of drugresistance and enhanced anti-MCL activity in murine and patient-derived xenograft models. This study integrated TME-mediated de-novo and acquired drug resistance mechanisms and provides the rationale for novel combination therapeutic strategy against MCL and other B cell malignancies.

2018-10-26 | PXD005734 | Pride

Comparative study of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in MCL

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A Novel Tumor suppressor network in squamous malignancies

Project description:The specific ablation of Rb1 gene in stratified epithelia (RbF/F;K14cre) promotes proliferation and altered differentiation but is insufficient to produce spontaneous tumors. The pRb relative, p107, compensates some of the functions of pRb in these tissues, however RbF/F;K14cre;p107-/- mice die postnatally. Acute pRb loss in stratified epithelia, using an inducible mouse model (RbF/F;K14creERTM), shows that p107 exerts specific tumor suppressor functions in its absence. After simultaneous absence of pRb and p107, p53 transcriptional function is impaired and Pten expression is reduced. All mutant mice develop spontaneous squamous tumors carcinomas rapidly. Gene expression analysis of mouse tumors, besides supporting the impaired p53 function and the susceptibility to Akt/mTOR inhibitors, also revealed significant overlap with human squamous carcinomas. Thus, RbF/F;K14creERTM;p107-/- may constitute a new mouse model for these malignancies. Collectively, these data demonstrate the existence of a previously unreported functional connection between pRb, Pten and p53 tumor suppressors, through p107, of a particular relevance in squamous tumor development. Gene expression was compared between normal mouse skin and carcinomas arising in the skin of RbF/F;K14creERTM;p107-/- mouse. All mice were treated with tamoxifen.

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Stable Cas9 Expression on Cell Growth Regulation Through mTORC2 Activation Facilitation

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