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Imatinib mesylate (Gleevec) in advanced breast cancer-expressing C-Kit or PDGFR-beta: clinical activity and
M Cristofanilli1, P Morandi, S Krishnamurthy
1Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. mcristof@mdanderson.org
Background:
Novel molecular therapies for metastatic breast cancer (MBC) are necessary to improve the dismal prognosis of this condition. Imatinib mesylate (Gleevec) inhibits several protein tyrosine kinases, including platelet-derived growth factor receptor (PDGFR) and c-kit, which are preferentially expressed in tumor cells. We tested the activity of imatinib mesylate in MBC with overexpression of PDGFR or c-kit. Additionally, we sought to determine the biological correlates and immunomodulatory effects.
Patients And Methods:
Thirteen patients were treated with Imatinib administered orally at 400 mg p.o. b.i.d. (800 mg/day), until disease progression. All patients demonstrated PDGFR-beta overexpression and none showed c-kit expression.
Results:
No objective responses were observed among the 13 patients treated in an intention-to-treat analysis. All patients experienced disease progression, with a median time to progression of 1.2 months. Twelve patients have died, and the median overall survival was 7.7 months. No patient had a serious adverse event. Imatinib therapy had no effect on the plasma levels of the angiogenesis-related cytokines, vascular endothelial growth factor, PDGF, b-fibroblast growth factor, and E-selectin. Immune studies showed imatinib inhibits interferon-gamma production by TCR-activated CD4(+) T cells.
Conclusion:
Imatinib as a single agent has no clinical activity in PDGFR-overexpressing MBC and has potential immunosuppressive effects.
Insights
Imatinib mesylate (Gleevec) showed no clinical activity in metastatic breast cancer (MBC) patients with PDGFR overexpression. The drug did not improve progression-free survival and may have immunosuppressive effects.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Metastatic breast cancer (MBC) requires novel therapies due to poor prognosis.
- Imatinib mesylate targets protein tyrosine kinases like platelet-derived growth factor receptor (PDGFR) and c-kit.
- PDGFR and c-kit are often overexpressed in tumor cells.
Purpose of the Study:
- To evaluate imatinib mesylate's efficacy in MBC with PDGFR or c-kit overexpression.
- To identify biological correlates of imatinib activity.
- To assess the immunomodulatory effects of imatinib.
Main Methods:
- Thirteen MBC patients with PDGFR-beta overexpression and no c-kit expression were treated with imatinib (800 mg/day).
- Treatment continued until disease progression.
- Objective responses, time to progression, overall survival, adverse events, cytokine levels, and immune cell function were assessed.
Main Results:
- No objective responses were observed in any of the 13 patients.
- All patients progressed, with a median time to progression of 1.2 months.
- Median overall survival was 7.7 months; imatinib did not affect angiogenesis-related cytokines but inhibited interferon-gamma production.
Conclusions:
- Imatinib as a single agent lacks clinical activity in PDGFR-overexpressing MBC.
- Imatinib may possess immunosuppressive properties, evidenced by reduced interferon-gamma production.
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