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Updated: Mar 9, 2026
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors
Tsuyoshi Takahashi1, Asmaa Elzawahry2,3, Sachiyo Mimaki4
1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2 E2, Yamadaoka, Suita City, Osaka, 565-0871, Japan.
Abstract:
Gastrointestinal stromal tumors represent the most common mesenchymal tumor of the digestive tract, driven by gain-of-function mutations in KIT. Despite its proven benefits, half of the patients treated with imatinib show disease progression within 2 years due to secondary resistance mutations in KIT. It remains unclear how the genomic and transcriptomic features change during the acquisition of imatinib resistance. Here, we performed exome sequencing and microarray transcription analysis for four imatinib-resistant cell lines and one cell line briefly exposed to imatinib. We also performed exome sequencing of clinical tumor samples. The cell line briefly exposed to imatinib exhibited few single-nucleotide variants and copy-number alterations, but showed marked upregulation of genes related to detoxification and downregulation of genes involved in cell cycle progression. Meanwhile, resistant cell lines harbored numerous genomic changes: amplified genes related to detoxification and deleted genes with cyclin-dependent kinase activity. Some variants in the resistant samples were traced back to the drug-sensitive samples, indicating the presence of ancestral subpopulations. The subpopulations carried variants associated with cell death. Pre-existing cancer cells with genetic alterations promoting apoptosis resistance may serve as a basis whereby cancer cells with critical mutations, such as secondary KIT mutations, can establish full imatinib resistance. © 2017 The Authors Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.
Insights
Gastrointestinal stromal tumors (GIST) develop imatinib resistance through genomic changes. Pre-existing resistance to apoptosis in cancer cells may enable secondary KIT mutations, leading to treatment failure.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Gastrointestinal stromal tumors (GIST) are common mesenchymal tumors driven by KIT mutations.
- Imatinib therapy is effective but often fails within two years due to secondary KIT resistance mutations.
- The genomic and transcriptomic changes during imatinib resistance acquisition are not fully understood.
Purpose of the Study:
- To investigate the genomic and transcriptomic alterations associated with imatinib resistance in GIST.
- To identify potential mechanisms underlying the development of secondary resistance mutations.
Main Methods:
- Exome sequencing and microarray transcription analysis of imatinib-resistant GIST cell lines.
- Exome sequencing of clinical GIST tumor samples.
- Analysis of genomic and transcriptomic changes in cell lines with varying imatinib exposure.
Main Results:
- Imatinib-resistant cell lines showed significant genomic changes, including amplification of detoxification genes and deletion of cyclin-dependent kinase genes.
- Early imatinib exposure led to upregulation of detoxification genes and downregulation of cell cycle genes.
- Ancestral subpopulations with variants promoting apoptosis resistance were identified in resistant samples, predating secondary KIT mutations.
Conclusions:
- Genomic and transcriptomic profiling reveals key changes during imatinib resistance development in GIST.
- Apoptosis resistance in pre-existing cancer cell subpopulations may provide a foundation for the emergence of full imatinib resistance.
- Understanding these mechanisms could lead to strategies to overcome or prevent imatinib resistance in GIST patients.
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