Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors

Cohen, Mark S.; Hussain, Hameda B.; Moley, Jeffrey F.

doi:10.1067/msy.2002.128562

Cited by 104 publications

(62 citation statements)

References 21 publications

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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: 48%

Current concepts in RET-related genetics, signaling and therapeutics

et al. 2006

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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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Section: Hirschsprung Combined With Men2mentioning

confidence: 48%

Current concepts in RET-related genetics, signaling and therapeutics

et al. 2006

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“…However, the drug showed poor activity in preclinical and clinical studies (Cohen et al 2002, de Groot et al 2007. In one attempt to improve its efficacy in MTC models, authors combined imatinib with a FGFR4 inhibitor (PD173074, Ezzat et al 2005).…”

Section: Combination Therapiesmentioning

confidence: 99%

Novel targeted therapeutics for MEN2

Plaza-Menacho

Mologni

2018

Endocrine-Related Cancer

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The rearranged during transfection (RET) proto-oncogene was recognized as the multiple endocrine neoplasia type 2 (MEN2) causing gene in 1993. Since then, much effort has been put into a clear understanding of its oncogenic signaling, its biochemical function and ways to block its aberrant activation in MEN2 and related cancers. Several small molecules have been designed, developed or redirected as RET inhibitors for the treatment of MEN2 and sporadic MTC. However, current drugs are mostly active against several other kinases, as they were not originally developed for RET. This limits efficacy and poses safety issues. Therefore, there is still much to do to improve targeted MEN2 treatments. New, more potent and selective molecules, or combinatorial strategies may lead to more effective therapies in the near future. Here, we review the rationale for RET targeting in MEN2, the use of currently available drugs and novel preclinical and clinical RET inhibitor candidates.

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“…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%

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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Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors

Cited by 104 publications

References 21 publications

Current concepts in RET-related genetics, signaling and therapeutics

Current concepts in RET-related genetics, signaling and therapeutics

Novel targeted therapeutics for MEN2

Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma

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