Cellular effects of imatinib on medullary thyroid cancer cells harboring multiple endocrine neoplasia Type 2A and 2B associated RET mutations

Groot, Jan Willem B. de; Plaza-Menacho, Iván; Schepers, Hein; Drenth-Diephuis, L. J.; Osinga, Jan; Plukker, John; Links, Th. P.; Eggen, Bart J. L.; Hofstra, Robert

doi:10.1016/j.surg.2005.10.019

Cited by 59 publications

(40 citation statements)

References 30 publications

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“…Selection of cells harbouring a RET mutation resistant to tyrosine kinase treatment might be an explanation for primary resistance in MTC. Another explanation for the relatively poor outcome may be that the dose of imatinib mesylate was too low to inhibit RET activity or phosphorylation, as suspected from in vitro studies (12). In comparison to other small-molecule kinase inhibitors of RET activity, imatinib exerts a low inhibition effect.…”

Section: Discussionmentioning

confidence: 99%

“…RET appears to be an excellent target for tyrosine kinase inhibitors like STI 571, ZD6474 and BAY 43-9006 (9), some of which are also effective inhibitors of vascular endothelial growth factor receptor 2. The growth of an MTC cell line (TT, human MTC cell line with a cys634trp heterozygous mutation) has been inhibited by different tyrosine kinase inhibitors in vitro and in an in vivo xenograft model (10)(11)(12). Imatinib (STI 571) inhibited the RET phosphorylation in two MTCderived cell lines in a dose-dependent manner (12).…”

Section: Introductionmentioning

confidence: 99%

“…The growth of an MTC cell line (TT, human MTC cell line with a cys634trp heterozygous mutation) has been inhibited by different tyrosine kinase inhibitors in vitro and in an in vivo xenograft model (10)(11)(12). Imatinib (STI 571) inhibited the RET phosphorylation in two MTCderived cell lines in a dose-dependent manner (12). However, the IC 50 , the concentration that causes 50% growth inhibition of imatinib necessary to inhibit RET in vitro is high when compared with other smallmolecule kinase inhibitors of RET activity (5,9).…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma

Frank‐Raue¹,

Fabel

Delorme

et al. 2007

eur j endocrinol

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Objective: Medullary thyroid carcinoma (MTC) is often associated with gain-of-function mutations in the RET proto-oncogene, which is found in all hereditary cases and most sporadic cases. The activated RET receptor tyrosine kinase can be inhibited by tyrosine kinase inhibitors in vitro. We evaluated the efficacy of treatment with imatinib mesylate, a tyrosine kinase inhibitor, in patients with advanced MTC. Design and patients:In this open-label clinical trial, nine patients, eight with sporadic and one with hereditary MTC, with unresectable, measurable, progressive metastases were treated with imatinib mesylate 600 mg daily. The tumour response to imatinib was evaluated after 3, 6 and 12 months by computed tomography and after 1 month by 18 F-fluoro-2-deoxy D-glucose position-emission tomographic scanning. The median duration of therapy was 8 months.Results: Overall, stable disease occurred in five patients for up to 6 months and in one patient for up to 12 months, with a median duration of progression-free survival of 6 months. Four patients had progressive disease after 12 months. One patient stopped therapy after 2 weeks because of worsening of diarrhoea. Therapy was well tolerated, although transient mild-to-moderate nausea (nZ3), oedema (nZ3), diarrhoea (nZ2) and skin rash (nZ2) were observed. Conclusion: Imatinib mesylate is well tolerated, no tumour remission was observed, only transient stable disease was achieved in some patients with advanced MTC.European Journal of Endocrinology 157 215-220

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma

Frank‐Raue¹,

Fabel

Delorme

et al. 2007

eur j endocrinol

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“…Imatinib (Glivec or Gleevec) shows inhibitory activity against RET-MEN2A and RET-MEN2B in MTC-derived cell lines and induces degradation of RET; however, the concentrations needed to inhibit cellular proliferation are high [69,70]. Encouraging results have been obtained with another tyrosine kinase inhibitor, BAY43-9006 [71], although resistance might become a problem, as has been previously demonstrated for RET [72].…”

Section: Hirschsprung Combined With Men2mentioning

confidence: 99%

Current concepts in RET-related genetics, signaling and therapeutics

et al. 2006

Self Cite

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The receptor tyrosine kinase RET is expressed in cell lineages derived from the neural crest and has a key role in regulating cell proliferation, migration, differentiation and survival during embryogenesis. Germline and somatic mutations in RET that produce constitutively activated receptors cause the cancer syndrome multiple endocrine neoplasia type 2 and several endocrine and neural-crest-derived tumors, whereas mutations resulting in nonfunctional RET or lower expression of RET are found in individuals affected with Hirschsprung disease. This review focuses on the genetics and molecular mechanisms underlying the different inherited human neural-crest-related disorders in which RET dysfunction has a crucial role and discusses RET as a potential therapeutic target. IntroductionThe human gene RET is localized on chromosome 10 (10q11.2) and contains 21 exons [1]; alternative splicing generates three isoforms, which contain 51 (RET51), 43 (RET43) and 9 (RET9) amino acids in the carboxyl (C)-terminal tail [2]. RET51 and RET9 are the most prevalent and best-characterized isoforms in vivo; RET43 has not yet been characterized. The RET51 isoform shows the highest transforming and kinase activity in vitro [3], and several observations suggest that these isoforms have different tissue-specific effects during embryogenesis [4]. Monoisoformic RET9 mice are viable and normal, whereas the monoisoformic RET51 mice (which lack RET9) have kidney hypoplasia and lack enteric ganglia from the colon [4].RET (Figure 1) is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands (GFLs): namely GDNF, Neurturin, Persephin and Artemin [5]. To stimulate RET, these GFLs first need to form a complex with their glycosylphosphatidylinositol (GPI)-anchored co-receptor, a member of the GDNF receptor-a family (GFRa1-GFRa4), after which the GFL-GFRa complex activates RET [6,7]. The GFRs differ in their specificity for GFLs (Figure 1).

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“…Surgical resection is the only effective treatment for these tumors (de Groot et al 2006, Deshpande et al 2011. Despite their relatively slow growth, MTCs are characterized by early metastatic spread, and the effective treatment of patients with advanced disease is still a major challenge (Ferreira & Maia 2013).…”

Section: Introductionmentioning

confidence: 99%

RET mutation and increased angiogenesis in medullary thyroid carcinomas

Verrienti¹,

Tallini²,

Colato³

et al. 2016

Endocrine-Related Cancer

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Advanced medullary thyroid cancers (MTCs) are now being treated with drugs that inhibit receptor tyrosine kinases, many of which involved in angiogenesis. Response rates vary widely, and toxic effects are common, so treatment should be reserved for MTCs likely to be responsive to these drugs. RET mutations are common in MTCs, but it is unclear how they influence the microvascularization of these tumors. We examined 45 MTCs with germ-line or somatic RET mutations (RETmut group) and 34 with wildtype RET (RETwt). Taqman Low-Density Arrays were used to assess proangiogenic gene expression. Immunohistochemistry was used to assess intratumoral, peritumoral and nontumoral expression levels of VEGFR1, R2, R3, PDGFRa, PDGFB and NOTCH3. We also assessed microvessel density (MVD) and lymphatic vessel density (LVD) based on CD31-positive and podoplanin-positive vessel counts, respectively, and vascular pericyte density based on staining for a-smooth muscle actin (a-SMA), a pericyte marker. Compared with RETwt tumors, RETmut tumors exhibited upregulated expression of proangiogenic genes (mRNA and protein), especially VEGFR1, PDGFB and NOTCH3. MVDs and LVDs were similar in the two groups. However, microvessels in RETmut tumors were more likely to be a-SMA positive, indicating enhanced coverage by pericytes, which play key roles in vessel sprouting, maturation and stabilization. These data suggest that angiogenesis in RETmut MTCs may be more intense and complete than that found in RETwt tumors, a feature that might increase their susceptibility to antiangiogenic therapy. Given their increased vascular pericyte density, RETmut MTCs might also benefit from combined or preliminary treatment with PDGF inhibitors. 23:8Research A Verrienti et al.Increased angiogenesis in RET-mutated MTCs RET mutation and increased angiogenesis in medullary thyroid carcinomas

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Cellular effects of imatinib on medullary thyroid cancer cells harboring multiple endocrine neoplasia Type 2A and 2B associated RET mutations

Cited by 59 publications

References 30 publications

Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma

Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma

Current concepts in RET-related genetics, signaling and therapeutics

RET mutation and increased angiogenesis in medullary thyroid carcinomas

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