AI-driven platform identifies dual inhibition of TNIK and CDK9 as effective targets for platinum resistant high-grade serous cancer
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PROVIDER: PRJNA1130485 | ENA |
REPOSITORIES: ENA
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Project description:Up to 90% of high grade serous ovarian cancer (HGSC) patients will become resistant to frontline platinum chemotherapy, necessitating innovative treatments for recurrent disease. Here we leveraged the Benevolent artificial intelligence (AI) PlatformTM in combination with in-silico modeling and patient-derived chemotherapy-resistant 3D models to identify dual targeting of TNIK and CDK9 as a promising therapeutic approach. Combined TNIK and CDK9 knockdown markedly diminished chemotherapy-resistant cell viability and inhibition of TNIK and CDK9 by NCB-0846 could sensitize platinum-resistant cells to cisplatin and showed efficacy against a panel of clinically validated HGSC organoids. Additionally, CDK9 was found to be a mediator of canonical Wnt activity which can drive progression and resistance across multiple cancers including HGSC. In sum, an innovative AI approach resulted in the identification of a druggable TNIK-CDK9 axis that can target chemotherapy-resistant HGSC, presenting a model for further drug development or patient stratification of CDK9 inhibitors in clinical trials.
2024-12-27 | GSE271224 | GEO
Project description:Wnt signalling maintains the undifferentiated state of intestinal crypt/progenitor cells through the TCF4/ß-catenin activating transcriptional complex. In colorectal cancer, activating mutations in Wnt pathway components lead to inappropriate activation of the TCF4/ß-catenin transcriptional program and tumourigenesis in the gut epithelium. The mechanisms by which TCF4/ß-catenin activate key target genes are not well understood. Using a proteomics approach, we identified Tnik, a member of the Germinal centre kinase family, as a Tcf4 interactor in the proliferative crypts of mouse small intestine. Tnik is recruited to promoters of Wnt target genes in mouse crypts and in Ls174T colorectal cancer cells in a ß-catenin dependent manner. Depletion of TNIK and expression of TNIK kinase mutants abrogated TCF-LEF transcription, highlighting the essential role of the kinase activity in Wnt target gene activation. siRNA depletion of TNIK followed by expression array analysis demonstrated that TNIK is an essential and exclusive activator of Wnt induced transcriptional program. As an essential component in the TCF4/ß-catenin activator complex, the kinase TNIK may present an attractive candidate for drug targeting in colorectal cancer.
2009-08-13 | GSE17623 | GEO
Project description:This study aims at correlating changes in the transcriptional state in high grade serous epithelial ovarian cancer (HGS-EOC) to the response to therapy, in particular the insurgence of resistance to platinum-based treatment.
2020-02-11 | E-MTAB-7083 | biostudies-arrayexpress
Project description:This study aims at correlating changes in the microRNA state in high grade serous epithelial ovarian cancer (HGS-EOC) to the response to therapy, in particular the insurgence of resistance to platinum-based treatment.
2020-02-11 | E-MTAB-7084 | biostudies-arrayexpress
Project description:Purpose: The goal of this study is to compare NGS-derived transcriptome profiling (RNA-seq) of naïve/ effector (D6)/ memory (D80) p14 T cell [wild-type (WT) and Tnik-/- (KO)] isolated form spleen of naïve or adoptively transferred and LCMV-WE immunized mice. Methods: Transcriptomic profiles of splenic naïve wild-type (WT) and Tnik-/- (KO) p14 T cells (8-week-old mice) or splenic effector (D6) and memory (D80) p14 T cells (post adoptive transfer and LCMV-WE immunization) were assessed in duplicates or triplicate by deep sequencing, using Illumina HiSeq 2500. qRT–PCR validation was performed using TaqMan and SYBR Green assays. Results: We mapped about 30 million sequence reads per sample to the mouse genome (GRCm38 - mm10) and identified expressed transcripts in splenic WT and Tnik−/− p14 T cells. RNA-seq data confirmed stable expression of known housekeeping genes. Differentially expressed genes between the WT and Tnik−/− p14 T cells from naïve, D6 or D80 were identified with a fold change ≥1.5 and p-value <0.05. Hierarchical clustering and gene ontology analysis of differentially expressed genes uncovered genes that may contribute to regulation of stemness, transcriptional regulation, cell cycle regulation, survival and function of T cells. Conclusions: Our study represents the first detailed transcriptome analysis of WT versus Tnik-/- p14 T cells in the context of acute viral infection, with biologic replicates, generated by RNA-seq technology. Our results show that TNIK regulates T cell fate. Evaluation of mRNA content in effector (D6) and memory (D80) p14 T cells revealed that TNIK-deficiency during T cell activation enhances proliferation, terminal differentiation and glycolysis of effector T cells, while compromising steady-state metabolic activity of memory T cells. We conclude that TNIK imprints memory formation early after CD8+ T cell priming.
2020-02-24 | GSE127734 | GEO
Project description:To evaluate the role of TNIK in ECs and in regulation of disturbed flow and laminar flow, we established Human Aorta (HAECs) from two human donnors in which each target gene has been knocked down of TNIK by siRNA. We then performed gene expression profiling analysis using data obtained from RNA-seq of two different HAECs witt/without knocking down of TNIK under disturb flow and laminar flow for 24 hours
2024-02-09 | GSE236529 | GEO
Project description:Wnt signalling maintains the undifferentiated state of intestinal crypt/progenitor cells through the TCF4/Ã-catenin activating transcriptional complex. In colorectal cancer, activating mutations in Wnt pathway components lead to inappropriate activation of the TCF4/Ã-catenin transcriptional program and tumourigenesis in the gut epithelium. The mechanisms by which TCF4/Ã-catenin activate key target genes are not well understood. Using a proteomics approach, we identified Tnik, a member of the Germinal centre kinase family, as a Tcf4 interactor in the proliferative crypts of mouse small intestine. Tnik is recruited to promoters of Wnt target genes in mouse crypts and in Ls174T colorectal cancer cells in a Ã-catenin dependent manner. Depletion of TNIK and expression of TNIK kinase mutants abrogated TCF-LEF transcription, highlighting the essential role of the kinase activity in Wnt target gene activation. siRNA depletion of TNIK followed by expression array analysis demonstrated that TNIK is an essential and exclusive activator of Wnt induced transcriptional program. As an essential component in the TCF4/Ã-catenin activator complex, the kinase TNIK may present an attractive candidate for drug targeting in colorectal cancer. HEK293T cells: Wnt3A vs control medium (CM) induction for 4, 7 and 9 hours; si-TNIK vs si-control after Wnt3A induction at 4 and 7 hours (2 biological replicates for 7 hour time point); dyeswap for each experiment (i.e. 12 arrays in total).
2010-08-18 | E-GEOD-17623 | biostudies-arrayexpress
Project description:Background: The potential of expression profiling using microarray analysis as a tool to predict the prognosis for different types of cancer has been realized. This study aimed to identify a novel biomarker for colorectal cancer (CRC). Methods: The expression profiles of cancer cells in 152 patients with stage I-III CRC were examined using microarray analysis. High expression in CRC cells, especially in patients with distant recurrences, was a prerequisite to select candidate genes. Thus, we identified eleven candidate genes, and selected Traf2- and Nck-interacting kinase (TNIK), which was known to be associated with progression in CRC through Wnt signaling pathways. We analyzed the protein expression of TNIK using immunohistochemistry (IHC) and investigated the relationship between protein expression and patient characteristics in 220 stage I-III CRC patients. Results: Relapse-free survival was significantly worse in the TNIK high expression group than in the TNIK low expression group in stage II (p = 0.028) and stage III (p = 0.006) patients. In multivariate analysis, high TNIK expression was identified as a significant independent risk factor of distant recurrence in stage III patients. Conclusion: This study is the first to demonstrate the prognostic significance of intratumoral TNIK protein expression in clinical tissue samples of CRC, in that high expression of TNIK protein in primary tumors was associated with distant recurrence in stage II and III CRC patients. This TNIK IHC study might contribute to practical decision-making in the treatment of these patients.
2016-07-22 | GSE71222 | GEO
Project description:Platinum-based chemotherapies are widely used anti-cancer drugs. Tumor resistance to platinum compounds is a major determinant of patient survival, including in high grade serous ovarian cancer (HGSOC). To understand mechanisms of platinum resistance and identify potential therapeutic targets in resistant HGSOC, we generated a comprehensive, reproducible data resource comprised of dynamic (+/-carboplatin) proteomic/posttranslational modification and RNASeq profiles from HGSOC intra-patient cell line pairs derived from 3 patients before and after acquiring platinum resistance. The molecular profiles revealed extensive responses to carboplatin and differential responses between sensitive and resistant cells. Higher oxidative phosphorylation and fatty acid oxidation (FAO) pathway expression were observed in the platinum-resistant cells, which was further validated in patient-derived xenograft (PDX) models. We show that both pharmacologic inhibition and CRISPR knockout of CPT1A, which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. Thus, FAO is a candidate therapeutic target to overcome platinum resistance.
2022-01-04 | GSE163152 | GEO