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9-ING-41, a small molecule inhibitor of GSK-3β, potentiates the effects of chemotherapy in KRAS mutated colorectal cancer

ABSTRACT: 9-ING-41, a small molecule inhibitor of GSK-3β, potentiates the effects of chemotherapy in KRAS mutated colorectal cancer

PROVIDER: PRJNA763229 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15898352_1.fastq.gz	Fastqsanger.gz
	SRR15898352_2.fastq.gz	Fastqsanger.gz
	SRR15898353_1.fastq.gz	Fastqsanger.gz
	SRR15898353_2.fastq.gz	Fastqsanger.gz
	SRR15898354_1.fastq.gz	Fastqsanger.gz

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9-ING-41, a small molecule inhibitor of GSK-3β, potentiates the effects of chemotherapy in KRAS mutated colorectal cancer

Project description:Despite the prevalence of KRAS mutations in colorectal cancer, there is no K-Ras targeted therapies for these tumors and available treatment options are limited for metastatic disease. GSK-3β has been demonstrated to be a critically important kinase for survival and proliferation of K-Ras-depended pancreatic cancer cells. In this study we tested 9-ING-41, a small molecule inhibitor of GSK-3β, in patient-derived tumor organoid models of colorectal cancer. We demonstrated that addition of 9-ING-41 to the standard of care drugs 5-FU and oxaliplatin could significantly enhance inhibition of the growth of colorectal cancer cells harboring KRAS mutations. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41-treated colorectal cancer cells. Moreover, we found substantial similarity in the changes of transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras-dependent cells. Overall, the results of this study provide a rationale for the inclusion of patients with mutant KRAS colorectal cancer in clinical studies of 9-ING-41 and other GSK-3 inhibitors.

2021-10-31 | GSE184125 | GEO

9-ING-41 in Patients With Advanced Cancers

Project description:GSK-3β is a potentially important therapeutic target in human malignancies. The Actuate 1801 Phase 1/2 study is designed to evaluate the safety and efficacy of 9-ING-41, a potent GSK-3β inhibitor, as a single agent and in combination with cytotoxic agents, in patients with refractory cancers.

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Impact of elraglusib (9-ING-41) treatment on gene expression in human colorectal cancer and immune cell lines.

Project description:A growing body of literature evaluates the potential anti-cancer and immunostimulatory effects of GSK-3 inhibition. Accordingly, we sought to evaluate GSK-3 inhibitor elraglusib (9-ING-41) and its impact on gene expression in both human colorectal cancer (CRC) cell lines and human immune cell lines. We used microarrays to detail the differential gene expression that occurs post-treatment with GSK-3 inhibitor 9-ING-41 (elraglusib).

2023-02-16 | GSE222849 | GEO

GSK-3β inhibition promotes engraftment of ex vivo expanded hematopoietic stem cells

Project description:Glycogen synthase kinase-3β (GSK-3β) has been recently identified as an important regulator of stem cell function. In vitro studies show that GSK-3β inhibition delays proliferation of human haematopoietic progenitor cells while increasing numbers of late dividing multipotent progenitors. Gene expression analysis revealed that GSK-3β inhibition modulates the expression of a subset of genes that are transcriptional targets for cytokines. GSK-3β inhibition antagonised down-regulation of genes encoding cyclin dependent kinase inhibitor p57 and a member of the growth arrest and DNA damage 45 family, GADD45B as well as up-regulation of cyclin D1 by cytokines, providing a possible mechanism for the BIO-induced delay in cell cycle progression. Surprisingly, inhibition of GSK-3β earlier shown to prevent β-catenin degradation and promote the nuclear accumulation of β-catenin was not sufficient to activate its transcriptional targets in haematopoietic stem cells. GSK-3β inhibition up-regulated the expression of a several positive regulators of stem cell function suppressed during cytokine-induced proliferation. The data supports a clinical role for GSK-3β inhibition to improve engraftment efficiency of ex vivo expanded stem cells.

2010-03-26 | GSE21073 | GEO

9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells.

Project description:Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new targeted therapy considering limited chemotherapy options. KRAS mutations are the most frequent molecular alterations in CRC. However, there are no approved K-Ras targeted therapies for these tumors yet. GSK-3β is demonstrated to be a critically important kinase for the survival and proliferation of K-Ras-dependent pancreatic cancer cells. In this study, we tested combinations of standard-of-care therapy and 9-ING-41, a small molecule inhibitor of GSK-3β, in CRC cell lines and patient-derived tumor organoid models of CRC. We demonstrate that 9-ING-41 inhibits the growth of CRC cells via a distinct from chemotherapy mechanism of action. Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41-treated CRC cells. Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras-dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC.

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Proteome and phosphoproteome analyses reveal the kinase regulatory network involved in glycogen synthesis kinase 3β

Project description:To analyze the roles of GSK-3β in podocytes, GSK-3β knockdown lentivirus by Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas)9 was applied to establish stable cell lines. Phosphoproteome and proteome evaluation was conducted using TMT labeled LC-MS/MS technologies.

2021-09-10 | PXD024543 | Pride

GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties.

Project description:Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

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9-ING-41, a small molecule inhibitor of GSK-3beta, potentiates the effects of anticancer therapeutics in bladder cancer.

Project description:Glycogen synthase kinase-3 beta (GSK-3β), a serine/threonine kinase, has been identified as a potential therapeutic target in human bladder cancer. In the present study, we investigated the antitumor effect of a small molecule GSK-3β inhibitor, 9-ING-41, currently in clinical studies in patients with advanced cancer, in bladder cancer cell lines. We found that treatment with 9-ING-41 leads to cell cycle arrest, autophagy and apoptosis in bladder cancer cells. The autophagy inhibitor chloroquine potentiated the antitumor effects of 9-ING-41 when tested in combination studies. Our findings also demonstrate that 9-ING-41 enhanced the growth inhibitory effects of gemcitabine or cisplatin when used in combination in bladder cancer cells. Finally, we found that 9-ING-41 sensitized bladder cancer cells to the cytotoxic effects of human immune effector cells. Our results provide a rationale for the inclusion of patients with advanced bladder cancer in clinical studies of 9-ING-41.

| S-EPMC6934761 | biostudies-literature

Nuclear GSK-3β and Oncogenic KRas Promote Aqp5+ Pancreatic Duct Stem Cell Expansion

Project description:Intraductal papillary mucinous neoplasm (IPMN) represents the most commonly diagnosed precursor lesion of pancreatic ductal adenocarcinoma (PDA), however the cell-of-origin remains unclear. Herein, we show that pancreas-specific activation in mice of nuclear-targeted glycogen synthase kinase-3β and oncogenic KRasG12D leads to the loss of acinar cells, the expansion of ductal cells, and the rapid development of IPMN with low-grade dysplasia. RNA-sequencing identified the expression of several ductal stem cell lineage genes including the water channel AQP5. The Aqp5+ pancreatic ductal cell pool was proliferative, phenotypically distinct from mature pancreatic ductal cells, and deletion of AQP5 limited IPMN development. Significantly, Aqp5 is highly expressed in human IPMN along with GSK-3b suggesting that human preneoplastic lesions likely arise from the expansion of an Aqp5+ pancreatic ductal stem cell. Altogether, these data identify Aqp5+ ductal cells in the mouse and human pancreas as the likely cell-of-origin for IPMN.

2022-03-22 | GSE169618 | GEO

Nuclear GSK-3β and Oncogenic KRas Promote Aqp5+ Pancreatic Duct Stem Cell Expansion

Project description:Nuclear GSK-3β and Oncogenic KRas Promote Aqp5+ Pancreatic Duct Stem Cell Expansion

| PRJNA717225 | ENA