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Updated: Jun 17, 2026
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Molecular mechanisms of secondary imatinib resistance in patients with gastrointestinal stromal tumors
Chun-Meng Wang1, Kai Huang, Ye Zhou
1Abdominal Department, Cancer Hospital, Fudan University, 270 Dong'an Road, 200032 Shanghai, People's Republic of China. cmwang1975@163.com
Aims And Background:
Most gastrointestinal stromal tumor (GIST) patients respond to KIT inhibition therapy of imatinib, but eventually become resistant with a median time to progression of 2 years. The mechanism of acquired resistance to imatinib and oncogenic KIT signal transduction in GISTs has not been well defined. We sought to investigate the spectrum of molecular and genomic changes in imatinib-resistant GIST patients.
Methods:
KIT and PDGFRA mutations were evaluated in 48 samples obtained from 32 GIST patients who underwent surgery after imatinib treatment. KIT downstream signaling profiles were also investigated in eight specimens of five patients who were clinically responsive or resistant to imatinib therapy. Biochemical inhibition of KIT, mitogen-activated protein kinase (MAPK), mammalian target of rapamycin (MTOR), AKT, proliferating cell nuclear antigen (PCNA) and BCL-2 were determined by western blotting for protein activation.
Results:
In all 32 GIST patients, activating mutations in the KIT gene were seen in 26 (81.3%) patients, PDGFRA gene mutations were seen in 2 (6.2%) patients and no primary mutations were found in 4 (12.5%) patients. Secondary KIT mutations were identified in 11/14 (78.6%) imatinib-acquired-resistance patients, with nine patients in KIT gene exon17, and the other two in exon 13. The expressions of p-KIT, p-AKT, PCNA and BCL-2 were higher in the samples of imatinib-resistant GISTs than those of imatinib-responsive ones. P-KIT, p-AKT expressions were higher in imatinib acquired-resistance GISTs with secondary KIT mutations than imatinib-responsive ones with primary mutation. Total KIT, MAPK, p-MAPK, p-MTOR expressions were comparable in all varied GISTs.
Conclusions:
Novel additional mutations of KIT gene exon 13 or exon 17 indicate the likely mechanism of secondary resistance to imatinib. The PI3-K/AKT pathway might be more relevant than MEK/MAPK for therapeutic targeting in imatinib-resistant GIST patients with secondary mutation.
Insights
Acquired resistance to imatinib in gastrointestinal stromal tumors (GIST) is often linked to secondary KIT mutations in exon 13 or 17. The PI3-K/AKT pathway appears more critical than MEK/MAPK for targeting resistant GIST. Keywords: GIST, imatinib resistance, KIT mutations, AKT pathway.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastrointestinal stromal tumors (GIST) commonly treated with imatinib, a KIT inhibitor, often develop acquired resistance.
- The precise molecular mechanisms driving imatinib resistance and KIT signaling in GIST remain incompletely understood.
Purpose of the Study:
- To investigate the molecular and genomic alterations associated with acquired imatinib resistance in GIST patients.
- To elucidate the signaling pathways involved in imatinib-resistant GIST.
Main Methods:
- Analysis of KIT and PDGFRA mutations in 32 GIST patients post-imatinib treatment.
- Evaluation of KIT downstream signaling (AKT, MAPK, MTOR) and protein expression (PCNA, BCL-2) via western blotting in responsive and resistant GIST samples.
Main Results:
- Activating KIT mutations were prevalent (81.3%), with secondary KIT mutations identified in 78.6% of imatinib-resistant cases, primarily in exon 17 and 13.
- Elevated expression of phosphorylated KIT (p-KIT) and phosphorylated AKT (p-AKT) observed in imatinib-resistant GISTs, particularly those with secondary KIT mutations.
- No significant differences in total KIT, MAPK, or MTOR expression across varied GIST groups.
Conclusions:
- Secondary mutations in KIT gene exons 13 or 17 represent a likely mechanism for acquired imatinib resistance in GIST.
- The PI3-K/AKT pathway is implicated as a more relevant therapeutic target than the MEK/MAPK pathway in imatinib-resistant GIST with secondary mutations.
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