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Updated: Mar 13, 2026
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Insights into ligand stimulation effects on gastro-intestinal stromal tumors signalling
Christelle Bahlawane1, Martine Schmitz1, Elisabeth Letellier1
1Molecular Disease Mechanisms group, Life Sciences Research Unit, University of Luxembourg, Campus Belval, 6 Avenue du Swing, L-4367 Belvaux, Luxembourg.
Abstract:
Mutations in KIT or PDGFRA are responsible for >85% of gastrointestinal stromal tumors. The introduction of imatinib in the GIST therapy scheme revolutionized the patient outcome. Unfortunately, the therapy allows the disease stabilization instead of curation. Furthermore the resistance to the inhibitor arises in most cases within two first years of therapy. A thorough investigation of the signalling pathways activated by the major PDGFRA and KIT mutants encountered in the GIST landscape allowed to identify striking differences between the two receptor tyrosine kinases. PDGFRA mutants were not responsive to their ligand, PDGFAA, and displayed a high constitutive kinase activity. In contrast, all KIT mutants retained, in addition to their constitutive activation, the ability to be stimulated by their ligand. Kit mutants displayed a lower intrinsic kinase activity relative to PDGFRA mutants, while the KIT Exon 11 deletion mutant exhibited the highest intrinsic kinase activity among KIT mutants. At the transcriptomic level, the MAPK pathway was established as the most prominent activated pathway, which is commonly up-regulated by all PDGFRA and KIT mutants. Inhibition of this pathway, using the MEK inhibitor PD0325901, reduced the proliferation of GIST primary cells at nanomolar concentrations. Altogether, our data demonstrate the high value of MEK inhibitors for combination therapy in GIST treatment and more importantly the interest of evaluating the SCF expression profile in GIST patients presenting KIT mutations.
Insights
Gastrointestinal stromal tumors (GIST) often develop resistance to imatinib therapy. Targeting the MAPK pathway with MEK inhibitors shows promise for combination therapy and evaluating SCF expression in KIT-mutated GIST patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Mutations in KIT or PDGFRA drive over 85% of gastrointestinal stromal tumors (GIST).
- Imatinib therapy revolutionized GIST treatment but often leads to resistance and disease stabilization rather than cure.
- Significant differences exist in the signaling pathways activated by PDGFRA and KIT mutants in GIST.
Purpose of the Study:
- To investigate the distinct signaling pathway activation by major PDGFRA and KIT mutants in GIST.
- To evaluate the efficacy of targeting the MAPK pathway in GIST primary cells.
- To explore the potential of MEK inhibitors and SCF expression analysis in GIST treatment strategies.
Main Methods:
- Comparative analysis of signaling pathways activated by PDGFRA and KIT mutants.
- Assessment of kinase activity and ligand responsiveness for different mutants.
- Transcriptomic analysis to identify prominent activated pathways.
- In vitro proliferation assays using MEK inhibitor PD0325901 on GIST primary cells.
Main Results:
- PDGFRA mutants showed high constitutive activity and ligand unresponsiveness, while KIT mutants retained ligand responsiveness alongside constitutive activation.
- KIT mutants exhibited lower intrinsic kinase activity than PDGFRA mutants, with the KIT Exon 11 deletion mutant showing the highest activity.
- The MAPK pathway was consistently upregulated by all PDGFRA and KIT mutants.
- MEK inhibitor PD0325901 significantly reduced GIST primary cell proliferation at nanomolar concentrations.
Conclusions:
- MEK inhibitors hold significant value for combination therapy in GIST treatment.
- Evaluating stem cell factor (SCF) expression profiles in GIST patients with KIT mutations is of clinical interest.
- Understanding differential pathway activation by KIT and PDGFRA mutants can inform personalized GIST therapy.
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