Imatinib Mesylate Inhibits Platelet-Derived Growth Factor Receptor Phosphorylation of Melanoma Cells But Does Not Affect Tumorigenicity In Vivo

McGary, Eric C.; Onn, Amir; Mills, Lisa D.; Heimberger, Amy B.; Eton, Omar; Thomas, Gary W.; Shtivelband, Mikhail; Bar‐Eli, Menashe

doi:10.1046/j.0022-202x.2004.22231.x

Cited by 49 publications

(46 citation statements)

References 22 publications

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“…No correlation between the receptor expression profile and the in vitro growth inhibition by imatinib could be detected. These results are in line with recently published data about melanoma-bearing athymic nude mice treated with imatinib without efficacy, regardless of whether the melanoma cells expressed PDGF-R or c-kit (McGary et al, 2004).…”

Section: Discussionsupporting

confidence: 82%

“…Thus, by inhibiting cell viability and proliferation via inhibition of receptor tyrosine kinases, imatinib might be a successful therapeutic in malignant melanoma. A first study investigating the growth behaviour of two human melanoma cell lines in athymic nude mice showed that imatinib treatment of these mice resulted in an inhibition of PDGF-R phosphorylation but no decrease in tumour size (McGary et al, 2004). In contrast, a recent report on murine B16F10 melanoma cells injected into C57B16 mice revealed a strong and efficient tumour growth inhibition by imatinib (Redondo et al, 2004).…”

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confidence: 94%

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Lack of clinical efficacy of imatinib in metastatic melanoma

et al. 2005

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This two-centre phase-II trial aimed at investigating the efficacy of imatinib in metastasised melanoma patients in correlation to the tumour expression profile of the imatinib targets c-kit and platelet-derived growth factor receptor (PDGF-R). The primary study end point was objective response according to RECIST, secondary end points were safety, overall and progression-free survival. In all, 18 patients with treatment-refractory advanced melanoma received imatinib 800 mg day À1. In 16 evaluable patients no objective responses could be observed. The median overall survival was 3.9 months, the median time to progression was 1.9 months. Tumour biopsy specimens were obtained from 12 patients prior to imatinib therapy and analysed for c-kit, PDGF-Ra and -Rb expression by immunohistochemistry. In four cases, cell lines established from these tumour specimens were tested for the antiproliferative effects of imatinib and for functional mutations of genes encoding the imatinib target molecules. The tumour specimens stained positive for CD117/c-kit in nine out of 12 cases (75%), for PDGF-Ra in seven out of 12 cases (58%) and for PDGF-Rb in eight out of 12 cases (67%). The melanoma cell lines showed a heterogenous expression of the imatinib target molecules without functional mutations in the corresponding amino-acid sequences. In vitro imatinib treatment of the cell lines showed no antiproliferative effect. In conclusion, this study did not reveal an efficacy of imatinib in advanced metastatic melanoma, regardless of the expression pattern of the imatinib target molecules c-kit and PDGF-R.

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Section: Discussionsupporting

confidence: 82%

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confidence: 94%

Lack of clinical efficacy of imatinib in metastatic melanoma

et al. 2005

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“…Pericytes express PDGFRB, and in normal angiogenesis, the recruitment of pericytes will stabilize neovessels [53]. MC are known to be able to express this same receptor [54], and in the present study, PDGFRB was specifically expressed by angiotropic MC in several human samples. Cancer stem cells are more resistant to therapy, and interestingly resistance to (V600E) B-RAF kinase inhibitor has been shown to be caused in part by MC upregulating PDGFRB [55].…”

Section: Discussionmentioning

confidence: 59%

Pilot Study on “Pericytic Mimicry” and Potential Embryonic/Stem Cell Properties of Angiotropic Melanoma Cells Interacting with the Abluminal Vascular Surface

Lugassy

Wadehra

et al. 2012

Cancer Microenvironment

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The interaction of tumor cells with the tumor vasculature is mainly studied for its role in tumor angiogenesis and intravascular metastasis of circulating tumor cells. In addition, a specific interaction of tumor cells with the abluminal surfaces of vessels, or angiotropism, may promote the migration of angiotropic tumor cells along the abluminal vascular surfaces in a pericytic location. This process has been termed extravascular migratory metastasis.The abluminal vascular surface may also provide a vascular niche inducing or sustaining stemness to angiotropic tumor cells. This pilot study investigated if angiotropic melanoma cells might represent a subset population with pericytic and embryonic or stem cell properties. Through microarray analysis, we showed that the interaction between melanoma cells and the abluminal surface of endothelial cells triggers significant differential expression of several genes. The most significantly differentially expressed genes have demonstrated properties linked to cancer cell migration (CCL2, ICAM1 and IL6), cancer progression (CCL2, ICAM1, SELE, TRAF1, IL6, SERPINB2 and CXCL6), epithelial to mesenchymal transition (CCL2 and IL6), embryonic/stem cell properties (CCL2, PDGFB, EVX1 and CFDP1) and pericytic recruitment (PDGFB). In addition, bioinformatics-based analysis of the differentially expressed genes has shown that the most significantly enriched functional groups included development, cell movement, cancer, and embryonic development. Finally, the investigation of pericyte/mesenchymal stem cells markers via immunostaining of human melanoma samples revealed expression of PDGFRB, NG2 and CD146 by angiotropic melanoma cells. Taken together, these preliminary data are supportive of the "pericytic mimicry" by angiotropic melanoma cells, and suggest that the interaction between melanoma cells and the abluminal vascular surface induce differential expression of genes linked to cancer migration and embryonic/ stem cell properties.

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“…In a murine B16F10 melanoma model, imatinib mesylate resulted in tumor growth inhibition (25). Furthermore, imatinib mesylate treatment of human melanoma xenografts in athymic nude mice has been shown to inhibit platelet-derived growth factor receptor phosphorylation albeit without reducing tumor size (26). Because imatinib mesylate targets both KIT and platelet-derived growth factor receptor activities, the relative roles of these two receptor tyrosine kinases in these models have yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Imatinib Targeting of KIT-Mutant Oncoprotein in Melanoma

Jiang

Zhou

Yuen

et al. 2008

Clinical Cancer Research

119

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Purpose: Melanoma subtypes based on anatomic location and UV light exposure can be further classified based on genetic alterations recently identified. Mutations and gene amplification in KIT have been described in a significant percentage of mucosal and acral melanomas. We recently reported a patient with metastatic mucosal melanoma harboring a known KIT mutation treated with imatinib mesylate who experienced a major response. Biological effects of KIT inhibition in these melanomas remain poorly understood. We sought to investigate further the effects of imatinib in these melanoma subsets. Experimental Design: Mucosal melanoma cells were analyzed for KIT aberrations by genomic sequencing, quantitative PCR, and single nucleotide polymorphism analyses. Imatinib effects were assayed by viability measurements and apoptotic cytotoxicity. Tumor cell lysates were assayed by Western blots to determine effects on multiple signaling pathways after imatinib exposure. Results: Mucosal melanoma cells exhibited imatinib sensitivity correlating with KIT mutational status. Imatinib dramatically decreased proliferation and was cytotoxic to a KIT mutated and amplified cell culture. Exposure to drug affected the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT, JAK-STAT, and antiapoptotic pathways. Conclusions: Rational targeting of KIT in melanoma offers a unique and potent clinical opportunity. In vitro analyses revealed major sensitivity to KIT kinase inhibition by imatinib, with potent induction of melanoma cell apoptosis. Biochemical studies identified changes in signaling molecules regulating proliferation and survival responses, which may serve as mediators and/or biomarkers of in vivo treatment efficacy. Pathways affected by KIT inhibition provide a model for understanding components in effective melanoma cell death and insights into targeting for resistance mechanisms.Melanomas arising from mucosal surfaces and from the palms, soles, and nailbeds do not result from the usual risk factors of sun exposure and family history (1). Few effective treatment options exist for patients who develop metastatic disease. Mucosal melanomas are rare and can arise in the sinuses, oropharynx, vagina, and anal regions (1). Acral melanomas (f5% of all melanomas) arise on non-hair-containing surfaces, such as palms, soles, and nailbeds (2). Given their unique distribution and similar incidence across races, mucosal and acral melanomas have been shown to harbor different genetic alterations and biological behavior compared with more common cutaneous melanomas (3, 4). Nonetheless, common with all subtypes of melanoma, few effective treatment options exist for patients who develop metastatic disease.Recently, gain-of-function KIT mutations were reported in 21% of mucosal melanomas, 11% of acral melanomas, and 16.7% of melanomas arising in chronically sun-damaged skin as indicated by the presence of solar elastosis (3). Other cases showed increased KIT copy number or amplification. In a separate report, 15% of anal m...

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Imatinib Mesylate Inhibits Platelet-Derived Growth Factor Receptor Phosphorylation of Melanoma Cells But Does Not Affect Tumorigenicity In Vivo

Cited by 49 publications

References 22 publications

Lack of clinical efficacy of imatinib in metastatic melanoma

Lack of clinical efficacy of imatinib in metastatic melanoma

Pilot Study on “Pericytic Mimicry” and Potential Embryonic/Stem Cell Properties of Angiotropic Melanoma Cells Interacting with the Abluminal Vascular Surface

Imatinib Targeting of KIT-Mutant Oncoprotein in Melanoma

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