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Protein kinase inhibitor-mediated immunoprophylactic and immunotherapeutic control of colon cancer

ABSTRACT: Protein kinase inhibitor-mediated immunoprophylactic and immunotherapeutic control of colon cancer

PROVIDER: PRJNA811154 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18165617.fastq.gz	Fastqsanger.gz
	SRR18165618.fastq.gz	Fastqsanger.gz
	SRR18165619.fastq.gz	Fastqsanger.gz
	SRR18165620.fastq.gz	Fastqsanger.gz
	SRR18165621.fastq.gz	Fastqsanger.gz

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Protein kinase inhibitor-mediated immunoprophylactic and immunotherapeutic control of colon cancer

Project description:An innovative multikinase inhibitor (H89)-based antitumor immunotherapy in colorectal cancer (CRC) is presented. The study was designed to evaluate the effect of H89 on colon tumor growth and carcinogenesis through in vivo analyses. Syngeneic mouse models of CRC cancer in BALB/c mice and chemically colon tumorigenesis, reveals that H89 delays colon oncogenesis, related to a preventive effect, and prevents tumor growth, underlying an antitumor effect respectively. Using immunodeficient and monoclonal antibody-specific immunosuppression, we identified immune cell populations involved in the preventive (NK-cell dependent) and antitumor activity of H89 (T-cell dependent). Flow cytometry analysis showed that the antitumor effect of H89 was correlated with an increase in the tumor microenvironment of CD4+ Th1 cells and CD8+ cytotoxic T cells and a decrease of CD4+ Treg cells infiltration. Furthermore, qRT-PCR revealed that H89 can promote naïve CD4+ T cells differentiation into Th1, decreases Treg differentiation and increases ex vivo CD8+ T cell-mediated killing of cancer cells. An RNAseq profiling experiment showed that H89 induces an overexpression of genes involved in antitumor immune response, such as IL-15RA, whose inhibition counteracts the antitumor effect of H89. In conclusion, our findings identify H89 as a potential strategy for the prevention and treatment of CRC.

2022-03-03 | GSE197598 | GEO

Protein Kinase Inhibitor-Mediated Immunoprophylactic and Immunotherapeutic Control of Colon Cancer.

Project description:Immunotherapy has allowed major advances in oncology in the past years, in particular with the development of immune checkpoint inhibitors, but the clinical benefits are still limited, particularly in colorectal cancer (CRC). Our scientific approach is based on the search for innovative immunotherapy with a final goal that aims to induce an effective antitumor immune response in CRC. Here, we focused on a multikinase inhibitor, H89. We carried out in vivo experiments based on syngeneic mouse models of colon cancer in BALB/c mice and chemically colon tumorigenesis. Flow cytometry, RNAseq, RT-qPCR, antibody-specific immune cell depletion, and Western blot were used to identify the immune cell type involved in the preventive and antitumor activity of H89. We demonstrated that H89 delays colon oncogenesis and prevents tumor growth. This latter effect seems to involve NK cells. H89 also inhibits colon tumor growth in a T-cell-dependent manner. Analysis of the immune landscape in the tumor microenvironment showed an increase of CD4+ Th1 cells and CD8+ cytotoxic T cells but a decrease of CD4+ Treg cell infiltration. Mechanistically, we showed that H89 could promote naïve CD4+ T-cell differentiation into Th1, a decrease in Treg differentiation, and an increase in CD8+ T-cell activation and cytotoxicity ex vivo. Furthermore, H89 induced overexpression of genes involved in antitumor immune response, such as IL-15RA, which depletion counteracts the antitumor effect of H89. We also found that H89 regulated Akt/PP2A pathway axis, involved in TCR and IL-15 signaling transduction. Our findings identify the H89 as a potential strategy for immune system activation leading to the prevention and treatment of CRC.

| S-EPMC9097540 | biostudies-literature

Tyrosine Kinase Inhibitor Cardiotoxicity

Project description:Tyrosine Kinase Inhibitor Cardiotoxicity

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CDK8 Mediator kinase drives colon cancer hepatic metastasis by regulating gene expression of the matrix metalloproteinase network [Illumina]

Project description:CDK8 Mediator kinase is amplified and overexpressed in colon cancers; elevated CDK8 expression is associated with shorter patient survival. Nevertheless, CDK8 kinase inhibitors do not generally suppress colon cancer growth. We addressed this paradox by investigating the effects of CDK8 knockdown or a CDK8 kinase inhibitor on tumor growth at primary and metastatic sites. CDK8 knockdown or inhibition had no significant effect on primary tumors but suppressed the growth of hepatic metastases in murine and human colon cancer models. The effect of CDK8 inhibition on liver metastasis is mediated by upregulation of matrix metalloproteinase (MMP) inhibitor TIMP3 and downregulation of several MMPs.

2017-10-16 | GSE104963 | GEO

CDK8 Mediator kinase drives colon cancer hepatic metastasis by regulating gene expression of the matrix metalloproteinase network [Affymetrix]

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AUTOPHAGY INHIBITION IMPROVES SENSITIVITY TO THE MULTI-KINASE INHIBITOR REGORAFENIB IN PRECLINICAL MOUSE COLON TUMOROIDS

Project description:AUTOPHAGY INHIBITION IMPROVES SENSITIVITY TO THE MULTI-KINASE INHIBITOR REGORAFENIB IN PRECLINICAL MOUSE COLON TUMOROIDS

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AUTOPHAGY INHIBITION IMPROVES SENSITIVITY TO THE MULTI-KINASE INHIBITOR REGORAFENIB IN PRECLINICAL MOUSE COLON TUMOROIDS

Project description:Colorectal cancer (CRC) remains the third leading cause of cancer-related deaths worldwide, with its incidence continuing to rise. Regorafenib, a multi-kinase inhibitor approved as a palliative treatment, extends survival in patients with metastatic CRC (mCRC) who have failed standard therapies. However, the clinical benefit of regorafenib is limited to a subset of patients, is typically short-lived, and is often accompanied by significant toxicity. The mechanisms by which CRC cells develop resistance to regorafenib remain poorly understood.In this study, we investigated resistance mechanisms to regorafenib using a preclinical mouse colon organoid model. Transcriptomic analysis of Apc wild-type and Apc-deficient organoids treated with regorafenib revealed an upregulation of epithelial-to-mesenchymal transition (EMT), accompanied by alterations in the secretome and increased activation of phosphorylated Erk1/2. Notably, co-treatment with an autophagy inhibitor suppressed regorafenib-induced EMT and its associated secretory phenotype, resulting in reduced cell proliferation and enhanced apoptosis in mouse organoids. The effectiveness of this drug combination was further supported by cell viability assays in human CRC cell lines. In contrast, primary mouse colon fibroblasts displayed greater resistance to both single-agent and combination regorafenib treatments. In summary, our findings using a preclinical organoid model suggest that autophagy inhibition may offer a promising strategy to mitigate chemoresistance and reduce toxicity associated with regorafenib treatment in mCRC patients.

2025-08-13 | GSE297312 | GEO

Expression of BRAF inhibitor resistant colon cancer lines

Project description:Colon cancer cell lines with partial sensitivity to the BRAF inhibitor PLX4720 were grown in increasing concentration of the drug to develop acquired resistance. Gene expression was performed for comparison of the resistant clones to the parental lines. Colon cancer cell lines with partial sensitivity to the BRAF inhibitor PLX4720 were grown in increasing concentration of the drug to develop acquired resistance. Gene expression was performed for comparison of the resistant clones to the parental lines.

2012-09-15 | E-GEOD-34299 | biostudies-arrayexpress

Kinase activity of nuclear TYRO3 promotes colon cancer malignancy

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Expression profiling, U2OS, Aurora kinase and p38 inhibitor response

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