ArticleBMC genomics2010
Causal reasoning identifies mechanisms of sensitivity for a novel AKT kinase inhibitor, GSK690693.
Article in BMC genomics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 36 citations in OpenAlex.
- MAVEN: compound mechanism of action analysis and visualisation using transcriptomics and compound structure data in R/Shiny.BMC bioinformatics · 2023Article
- Benchmarking causal reasoning algorithms for gene expression-based compound mechanism of action analysis.BMC bioinformatics · 2023Article
- Computational analyses of mechanism of action (MoA): data, methods and integration.RSC chemical biology · 2022Review
- A nontoxic fungal natural product modulates fin regeneration in zebrafish larvae upstream of FGF-WNT developmental signaling.Developmental dynamics : an official publication of the American Association of Anatomists · 2021Article
- Treatment With Suboptimal Dose of Benznidazole Mitigates Immune Response Molecular Pathways in Mice With Chronic Chagas Cardiomyopathy.Frontiers in cellular and infection microbiology · 2021Article
- Using microRNA Networks to Understand Cancer.International journal of molecular sciences · 2018Review
- Expanding primary cells from mucoepidermoid and other salivary gland neoplasms for genetic and chemosensitivity testing.Disease models & mechanisms · 2018Article
- Transcription factor HBP1 is a direct anti-cancer target of transcription factor FOXO1 in invasive oral cancer.Oncotarget · 2017Article
- Construction of biological networks from unstructured information based on a semi-automated curation workflow.Database : the journal of biological databases and curation · 2015Article
- Causal analysis approaches in Ingenuity Pathway Analysis.Bioinformatics (Oxford, England) · 2014Article
- Leveraging systems biology approaches in clinical pharmacology.Biopharmaceutics & drug disposition · 2013Review
- Reverse causal reasoning: applying qualitative causal knowledge to the interpretation of high-throughput data.BMC bioinformatics · 2013Article
- Novel pancreatic endocrine maturation pathways identified by genomic profiling and causal reasoning.PloS one · 2013Article
- Assessment of network perturbation amplitudes by applying high-throughput data to causal biological networks.BMC systems biology · 2012Article
- Determination of minimal transcriptional signatures of compounds for target prediction.EURASIP journal on bioinformatics & systems biology · 2012Article
- AKT signaling pathway activated by HIN-1 methylation in non-small cell lung cancer.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2012Article
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- Construction of a computable cell proliferation network focused on non-diseased lung cells.BMC systems biology · 2011Article
- GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt.Clinical cancer research : an official journal of the American Association for Cancer Research · 2010Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundInappropriate activation of AKT signaling is a relatively common occurrence in human tumors, and can be caused by activation of components of, or by loss or decreased activity of inhibitors of, this signaling pathway. A novel, pan AKT kinase inhibitor, GSK690693, was developed in order to interfere with the inappropriate AKT signaling seen in these human malignancies. Causal network modeling is a systematic computational analysis that identifies upstream changes in gene regulation that can serve as explanations for observed changes in gene expression. In this study, causal network modeling is employed to elucidate mechanisms of action of GSK690693 that contribute to its observed biological effects. The mechanism of action of GSK690693 was evaluated in multiple human tumor cell lines from different tissues in 2-D cultures and xenografts using RNA expression and phosphoproteomics data. Understanding the molecular mechanism of action of novel targeted agents can enhance our understanding of various biological processes regulated by the intended target and facilitate their clinical development.
resultsCausal network modeling on transcriptomic and proteomic data identified molecular networks that are comprised of activated or inhibited mechanisms that could explain observed changes in the sensitive cell lines treated with GSK690693. Four networks common to all cell lines and xenografts tested were identified linking GSK690693 inhibition of AKT kinase activity to decreased proliferation. These networks included increased RB1 activity, decreased MYC activity, decreased TFRC activity, and increased FOXO1/FOXO3 activity.
conclusionAKT is involved in regulating both cell proliferation and apoptotic pathways; however, the primary effect with GSK690693 appears to be anti-proliferative in the cell lines and xenografts evaluated. Furthermore, these results indicate that anti-proliferative responses to GSK690693 in either 2-D culture or xenograft models may share common mechanisms within and across sensitive cell lines.
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