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Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
New insights into the clinical management of advanced gastrointestinal stromal tumors
1Department of Medicine, Bergonié Institute, Bordeaux.
Introduction:
90% of gastrointestinal stromal tumors (GISTs) harbor an activating mutation in the KIT or PDGFRα oncogene, and these are known to confer imatinib sensitivity.
Areas Covered:
The author reviews the data regarding the current management of GIST, mechanisms of resistance to imatinib, and new drugs currently in clinical development and provides his unique perspectives on the subject matter.
Expert Opinion:
Several studies have shown that the response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFRα. Moreover, most, if not all, patients treated with imatinib for advanced GIST will develop a secondary progressive disease under the treatment. In most cases, such progressions are the result of acquired resistance due to the occurrence of secondary c-KIT mutations, especially in GISTs with primary exon 11 mutations. Sunitinib and regorafenib are inhibitors of multiple tyrosine kinases, including KIT, PDGFRα, PDGFRβ, and VEGFRs, and are approved for the management of imatinib- and imatinib/sunitinib-refractory GIST patients, respectively. Clearly, better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors such as avapritinib and ripretinib will provide new individualized therapeutic strategies for GIST patients.
Insights
Gastrointestinal stromal tumors (GISTs) often have KIT or PDGFRα mutations, making them sensitive to imatinib. However, resistance develops, necessitating new therapies like avapritinib and ripretinib for improved GIST treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gastrointestinal stromal tumors (GISTs) are frequently driven by activating mutations in the KIT or PDGFRα oncogenes.
- These mutations are known to predict sensitivity to imatinib therapy.
Purpose of the Study:
- To review current management strategies for GIST.
- To explore mechanisms of imatinib resistance in GIST.
- To discuss novel drugs in clinical development for GIST.
Main Methods:
- Literature review of GIST management.
- Analysis of imatinib resistance mechanisms.
- Evaluation of emerging tyrosine kinase inhibitors.
Main Results:
- GIST patient response to imatinib is strongly linked to KIT or PDGFRα mutational status.
- Most patients with advanced GIST develop secondary resistance to imatinib.
- Acquired resistance often results from secondary c-KIT mutations, particularly in tumors with primary exon 11 mutations.
Conclusions:
- Sunitinib and regorafenib are approved for refractory GIST but resistance remains a challenge.
- Understanding imatinib resistance mechanisms is crucial for developing new therapies.
- Next-generation inhibitors like avapritinib and ripretinib offer potential for individualized GIST treatment strategies.
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