Dataset Information

Why tyrosine kinase inhibitor resistance is common in advanced gastrointestinal stromal tumors.

ABSTRACT:

Background

Most patients with advanced gastrointestinal stromal tumors (GIST) develop drug resistance to tyrosine kinase inhibitors (TKIs) within two years of starting therapy, whereas most chronic myeloid leukemia (CML) patients in chronic phase still exhibit disease control after a decade on therapy. This article aims to explain this divergence in long term outcomes.

Methods and results

By combining clinical and experimental observations with mathematical formulas we estimate that, in advanced GIST, the genetic changes responsible for resistance are generally already present at disease detection.

Conclusion

This result has relevant clinical implications by providing support for the exploration of combination therapies.

SUBMITTER: Tomasetti C

PROVIDER: S-EPMC3892920 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Why tyrosine kinase inhibitor resistance is common in advanced gastrointestinal stromal tumors.

Tomasetti Cristian C Demetri George D GD Parmigiani Giovanni G

F1000Research 20130709

<h4>Background</h4>Most patients with advanced gastrointestinal stromal tumors (GIST) develop drug resistance to tyrosine kinase inhibitors (TKIs) within two years of starting therapy, whereas most chronic myeloid leukemia (CML) patients in chronic phase still exhibit disease control after a decade on therapy. This article aims to explain this divergence in long term outcomes.<h4>Methods and results</h4>By combining clinical and experimental observations with mathematical formulas we estimate th ...[more]

PMID: 24555070

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Project description:BackgroundGastrointestinal stromal tumor (GIST) is a common tumor that originates from the alimentary system mesenchyme. Compared to typical gastrointestinal carcinomas, GISTs exhibit unique malignant behaviors. Bioinformatic tools and subsequent experiments were applied to investigate novel targets involved in GIST progression and imatinib resistance.MethodsDifferences in gene expression profiles between advanced and nonadvanced GISTs were comprehensively analyzed based on the Gene Expression Omnibus (GEO) dataset GSE136755. A protein-protein interaction (PPI) network was constructed to identify the potential target gene. Gene set enrichment analysis (GSEA) was used to elucidate relevant biological events related to the target gene based on the GSE47911 dataset. Subsequently, immunohistochemistry and Kaplan-Meier analysis were performed to validate the prognostic value of the target gene in GISTs. Overexpression of the target gene was conducted to analyze its function in the proliferation, apoptosis, and imatinib resistance of GIST/T1 cells.ResultsIn the current study, a total of 606 differentially expressed genes (DEGs) were screened based on the GSE136755 dataset, and the upregulated DEGs in advanced GISTs were mainly involved in cell division through functional annotations. The intersecting hub gene, Aurora kinase A (AURKA), was identified by degree and bottleneck algorithms. GSEA revealed that AURKA was involved in cell cycle-related biological processes. Analysis of the Oncomine and GEPIA databases revealed a pattern of elevated AURKA expression in most human malignances. Clinical assays demonstrated that AURKA could be an independent prognostic factor for GISTs. Additionally, overexpression of AURKA was experimentally demonstrated to promote cell proliferation, inhibit cell apoptosis, and enhance imatinib resistance in GIST/T1 cells.ConclusionsThese findings indicated that overexpression of AURKA promoted GIST progression and enhanced imatinib resistance, implying that AURKA is a potential therapeutic target for GISTs.

Dataset Information

Why tyrosine kinase inhibitor resistance is common in advanced gastrointestinal stromal tumors.

Background

Methods and results

Conclusion

Publications

Why tyrosine kinase inhibitor resistance is common in advanced gastrointestinal stromal tumors.

Similar Datasets

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