Inhibition of KIT Tyrosine Kinase Activity: A Novel Molecular Approach to the Treatment of KIT-Positive Malignancies

Heinrich, Michael C.; Blanke, Charles D.; Druker, Brian J.; Corless, Christopher L.

doi:10.1200/jco.20.6.1692

Cited by 444 publications

(227 citation statements)

References 93 publications

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“…PDGFRs, as well as KIT, belong to the type III receptor tyrosine kinases, and can be specifically treated by tyrosine kinase inhibitors such as imatinib mesylate (STI571). 22 A recent study has demonstrated that imatinib mesylate inhibits ovarian cancer cell proliferation and PDGF-induced S-phase entry through PDGFR-a and Akt inactivation. 23 Although a phase II trial of imatinib mesylate as a single agent failed to produce satisfactory efficacy against recurrent and platinum-resistant ovarian cancer, 24 cases with clear-cell adenocarcinoma were not enrolled and, therefore, the effect of imatinib or other tyrosine kinase inhibitors on ovarian clear-cell adenocarcinoma remains undetermined.…”

Section: Discussionmentioning

confidence: 99%

Expression of platelet-derived growth factors and their receptors in ovarian clear-cell carcinoma and its putative precursors

et al. 2008

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Recent studies have shown that platelet-derived growth factors and their receptors are frequently co-expressed in ovarian cancers. Herein, we investigated the role of the platelet-derived growth factor pathway in the development of ovarian clear-cell adenocarcinoma, a highly chemoresistant form of ovarian cancer. Immunohistochemical expression of platelet-derived growth factor receptor-a and receptor-b, platelet-derived growth factor A-chain and B-chain was examined in 31 cases of clear-cell adenocarcinoma and 56 coexisting putative precursor lesions: 17 non-atypical and 19 atypical endometrioses, and 10 non-atypical and 10 atypical clear-cell adenofibroma components. Twenty-one solitary endometrioses were also examined. Vascular endothelial cells were always positive for all the markers examined, and were used as positive controls. The frequencies of positivity for platelet-derived growth factor receptor-a and receptor-b, and platelet-derived growth factor A-chain increased in accordance with higher cytologic atypia in the putative precursors: 71, 47, and 59% in the 17 non-atypical endometrioses, 84, 73, and 84% in the 19 atypical endometrioses, 0% each in the 10 non-atypical clear-cell adenofibromas, 100, 90, and 90% in the 10 atypical clear-cell adenofibromas, and 97, 97, and 100% in the 31 clear-cell adenocarcinomas, respectively. Positivity for platelet-derived growth factor B-chain increased in accordance with increased atypia in clear-cell adenofibroma: 0% in non-atypical clear-cell adenofibromas, 30% in atypical clear-cell adenofibromas, and 60% in coexisting carcinomas. However, in contrast, positivity for platelet-derived growth factor B-chain decreased in accordance with increased atypia in endometriosis coexisting with clear-cell adenocarcinomas: 35% in non-atypical endometrioses, 11% in atypical endometrioses, and 5% in coexisting carcinomas. Platelet-derived growth factor receptor-a and receptor-b, and their ligands A-chain and B-chain were positive in 14, 29, 19, and 62% of the solitary endometrioses, respectively. These results indicate activation of the platelet-derived growth factor pathway in ovarian clear-cell adenocarcinomas and suggest biological differences between carcinomas that arise in association with clearcell adenofibroma vs endometriosis.

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Section: Discussionmentioning

confidence: 99%

Expression of platelet-derived growth factors and their receptors in ovarian clear-cell carcinoma and its putative precursors

et al. 2008

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“…However, the higher rate of c-kit expression in malignant phyllodes tumors in our study was comparable to these series. 9,10 In view of the action of the newly developed phenylaminopyrimidine derivative STI571 (Glivec, Novartis), which inhibits tyrosine kinase receptors, and its usefulness in gastrointestinal stromal tumors, 21 the drug may theoretically also be useful in the management of malignant phyllodes tumor, particularly with tumor recurrences or distant metastases.…”

Section: Discussionmentioning

confidence: 99%

Increased c-kit (CD117) expression in malignant mammary phyllodes tumors

et al. 2004

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Mammary phyllodes tumors are uncommon stromal neoplasms, and are divided into benign, borderline and malignant groups basing on histologic criteria. While benign phyllodes tumors may recur, borderline phyllodes tumors show higher propensity to recur locally and rarely metastasize, and malignant phyllodes tumors show even higher chances of local recurrences or distant metastases. c-kit is a proto-oncogene that encodes a tyrosine kinase receptor (CD117) and is a marker for gastrointestinal stromal tumors (GIST). With the advent of therapeutic agent targeted at this receptor for GIST, we investigated 179 phyllodes tumors (101 benign, 50 borderline, 28 malignant) for c-kit expression using immunohistochemistry. The staining was compared to the degree of malignancy, and to the degree of stromal cellularity, mitotic activity, nuclear pleomorphism and stromal overgrowth. The overall positive rate for c-kit was 29% (52/179) and 17% (17/101), 24% (12/50) and 46% (13/28), respectively, for benign, borderline malignant and frank malignant phyllodes and the differences between all categories were significant (v 2 ¼ 13.844, P ¼ 0.001). In mammary phyllodes tumors, there was increasing c-kit expression with increasing degree of malignancy, up to 46% in malignant cases. This provides strong evidence that c-kit receptor mediated tyrosine kinase involvement in the pathogenesis of phyllodes tumors, and the therapeutic agent, STI571, Glivec, may be a potentially useful drug for its management.

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“…In some cancers such as gastro intestinal stromal tumours (GISTs), point mutations lead to abnormal expression and constitutive activity of the receptor. CD117 is targeted there by imatimib mesylate (Heinrich et al, 2002).…”

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confidence: 99%

Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer

et al. 2005

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Squamous cell carcinoma of the oesophagus (SCCO) is still a pathology of bad prognosis. Specific therapies are now developed against epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, c-kit receptor (CD117), vascular endothelial growth factor (VEGF) and p53 protein. This study was aimed at assessing their expression in a large series of SCCO, as well as their potential therapeutic interest in this pathology. Immunohistochemical expression of these factors was assessed retrospectively in 107 cases of SCCO with primary surgery, as well as their relationships to recurrence, metastasis and overall survival on a long-term follow-up. Human epidermal growth factor receptor 2 and CD117 were expressed in less than 3% of the cases. Epidermal growth factor receptor and p53 were overexpressed in 68.2 and 66.4% of the cases, and VEGF in 38.3%. Epidermal growth factor receptor overexpression was significantly related to vascular invasion (P ¼ 0.023). Its diffuse positivity was significantly related in multivariate analysis to higher local recurrence (P ¼ 0.006) and lower overall survival (P ¼ 0.003), in a subgroup of patients of poor outcome who had received postoperative adjuvant treatment. These results highlight the great potential prognostic and therapeutic interest of evaluating EGFR diffuse positivity in locally advanced SCCO.

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Inhibition of KIT Tyrosine Kinase Activity: A Novel Molecular Approach to the Treatment of KIT-Positive Malignancies

Cited by 444 publications

References 93 publications

Expression of platelet-derived growth factors and their receptors in ovarian clear-cell carcinoma and its putative precursors

Expression of platelet-derived growth factors and their receptors in ovarian clear-cell carcinoma and its putative precursors

Increased c-kit (CD117) expression in malignant mammary phyllodes tumors

Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer

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