Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor

Heinrich, Michael C.; Corless, Christopher L.; Demetri, George D.; Blanke, Charles D.; Mehren, Margaret von; Joensuu, Heikki; McGreevey, Laura; Chen, Chang Jie; Abbeele, Annick D. Van den; Druker, Brian J.; Kiese, Beate; Eisenberg, Burton L.; Roberts, Peter; Singer, Samuel; Fletcher, Christopher D.�M.; Silberman, Sandra; Dimitrijević, Saša; Fletcher, Jonathan A.

doi:10.1200/jco.2003.04.190

Cited by 2,122 publications

(1,674 citation statements)

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“…Furthermore, a recent study demonstrated that in late-stage metastatic GIST, different mutations within the KIT gene resulted in different STI571 effectiveness. 20 In malignant phyllodes tumors, as the lesional cells are also stromal in origin, an understanding or a more comprehensive assessment of the c-kit expression in phyllodes tumors may be crucial for possible future use of STI571 in these tumors. However, as the effectiveness in other soft-tissue tumor of STI571 has not been conclusively demonstrated, it is still too early to speculate on its role in mammary phyllodes tumors.…”

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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“…20 Another tumor that commonly expresses KIT is gastrointestinal stromal tumor (GIST). 21 Successful treatment of metastatic and unresectable GIST with the ATP-competitive protein kinase inhibitor, imatinib mesylate (Gleevec), 22,23 has prompted a search for activating mutations in KIT and related receptor tyrosine kinases in Merkel cell carcinoma. In vitro studies have shown a decrease in proliferation of Merkel cell carcinoma by addition of Gleevec.…”

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confidence: 99%

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Kartha

Sundram

2008

Modern Pathology

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Merkel cell carcinoma is a rare and aggressive form of skin cancer of neuroendocrine origin. Its treatment involves wide excision and radiotherapy but no effective therapy exists for advanced disease. Upregulation of the platelet-derived growth factor receptor family of tyrosine kinases, PDGFRA and KIT, has a crucial role in cancer development. Several studies have shown expression of the tyrosine kinase receptor KIT (CD117) in Merkel cell carcinoma. In this study, we examined the expression and mutational status of KIT and PDGFRA in 14 primary and 18 metastatic Merkel cell carcinoma. The expression of KIT and PDGFRA and their respective ligands, stem cell factor (SCF) and PDGFA, was assessed by immunohistochemistry. In addition, we analyzed KIT exons 9, 11, 13 and 17, and PDGFRA exons 10, 12 and 18 for the presence of activating mutations. We found that only 53% of cases of Merkel cell carcinoma expressed KIT, which was mostly seen as diffuse weak staining, and SCF expression was observed only in 31% of cases. In contrast, 87 and 81% of cases expressed PDGFRA and PDGFA, respectively. We observed coexpression of SCF and KIT in only 5 of 32 cases (16%) whereas 25 of 31 cases (81%) showed coexpression of PDGFRA and its ligand PDGFA. While we documented silent mutations in exon 17 of KIT and exons 10, 12 and 18 of PDGFRA, we were not able to identify any known activating mutations. Our results indicate that there is no correlation between positive immunostaining and occurrence of activating mutations in KIT and PDGFRA. Moreover, the presence of KIT/SCF and PDGFRA/PDGFA coexpression in a proportion of cases may indicate an autocrine/paracrine stimulation loop. We think therefore that imatinib mesylate is less likely to be an effective therapy for Merkel cell carcinoma, unless activating mutations exist in other exons of these receptor kinases.

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“…In both the receptors, the mechanism responsible for kinase activation is mainly represented by gain-of-function mutations, which always affect specific exons (Corless et al, 2004). To date, several types of mutations have been described and the main mutational 'hot spot' is represented by c-Kit exon 11 (Corless et al, 2002;Heinrich et al, 2003).…”

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Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients

et al. 2006

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Imatinib-acquired resistance related to the presence of secondary point mutations has become a frequent event in gastrointestinal stromal tumors. Here, transient transfection experiments with plasmids carrying two different KIT-acquired point mutations were performed along with immunoprecipitation of total protein extracts, derived from imatinib-treated and untreated cells. The molecular mechanics/Poisson Boltzmann surface area computational techniques were applied to study the interactions of the wild-type and mutated receptors with imatinib at the molecular level. Biochemical analyses showed KIT phosphorylation in cells transfected with vectors carrying the specific mutant genes. Imatinib treatment demonstrated that T670I was insensitive to the drug at all the applied concentrations, whereas V654A was inhibited by 6 lM of imatinib. The modeling of the mutated receptors revealed that both substitutions affect imatinib-binding site, but to a different extent: T670I substantially modifies the binding pocket, whereas V654A induces only relatively confined structural changes. We demonstrated that T670I and V654A cause indeed imatinib-acquired resistance and that the former is more resistant to imatinib than the latter. The application of molecular simulations allowed us to quantify the interactions between the mutated receptors and imatinib, and to propose a molecular rationale for this type of drug resistance.

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Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor

Abstract: Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.

Cited by 2,122 publications

References 36 publications

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

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

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients

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