Multiple endocrine neoplasia type 2B mutation in human RET oncogene induces medullary thyroid carcinoma in transgenic mice

Acton, Dennis S.; Velthuyzen, Danny; Lips, Cornelis J.M.; Höppener, Jo W.M.

doi:10.1038/sj.onc.1203648

Cited by 76 publications

(48 citation statements)

References 20 publications

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“…These data imply the existence of second-site mutations that modulate how different families and individuals manifest MEN2. Ret MEN2 mouse models show substantial variation in the penetrance of tumors depending on genetic background effects, again suggesting a requirement for secondary genetic alterations for malignant transformation by Ret MEN2 (Michiels et al 1997;Acton et al 2000;Kawai et al 2000;Smith-Hicks et al 2000;Cranston and Ponder 2003).…”

Section: Genementioning

confidence: 99%

“…Tissue culture studies have implicated numerous signaling pathways, but little is known about the relevance of these pathways in vivo. Moreover, both MEN2 families and MEN2 mouse models display significant phenotypic variation, although the basis for this variation remains largely unexplored (Eng et al 1996;Michiels et al 1997;Acton et al 2000;Kawai et al 2000;Smith-Hicks et al 2000;Cranston and Ponder 2003). Little is known about possible secondary mutations that promote MEN2-associated tumors.…”

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confidence: 99%

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A Drosophila Model of Multiple Endocrine Neoplasia Type 2

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et al. 2005

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Dominant mutations in the Ret receptor tyrosine kinase lead to the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that Ret MEN2 mutations significantly alter Ret-signaling properties, but the precise mechanisms by which Ret MEN2 promotes tumorigenesis remain poorly understood. To determine the signal transduction pathways required for Ret MEN2 activity, we analyzed analogous mutations in the Drosophila Ret ortholog dRet. Overexpressed dRet MEN2 isoforms targeted to the developing retina led to aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analysis indicated that dRet MEN2 acts through the Ras-ERK, Src, and Jun kinase pathways. A genetic screen for mutations that dominantly suppress or enhance dRet MEN2 phenotypes identified new genes that are required for the phenotypic outcomes of dRet MEN2 activity. Finally, we identified human orthologs for many of these genes and examined their status in human tumors. Two of these loci showed loss of heterozygosity (LOH) within both sporadic and MEN2-associated pheochromocytomas, suggesting that they may contribute to Ret-dependent oncogenesis. D URING development, receptor tyrosine kinases (RTKs) integrate extracellular signals to influence cellular processes such as growth and differentiation. Signaling through RTKs requires ligand-induced oligomerization to direct tyrosine autophosphorylation; autophosphorylation both stimulates catalytic activity and creates phospho-tyrosine docking sites for cytoplasmic proteins that activate intracellular signaling pathways. To date, mutations in more than half of all RTKs have been implicated in human cancer (reviewed in Blume-Jensen and Hunter 2001). These mutations commonly function by relieving RTK regulatory constraints, leading to inappropriate kinase activity and hyperactivation of downstream pathways. These events promote oncogenic transformation by driving aberrant cellular growth, proliferation, and survival. Still, tumorigenesis requires mutations in multiple loci: along with dominant mutations in oncogenes such as RTKs, tumorigenesis also requires loss-of-function mutations in tumor suppressors. The relationship between oncogenic tyrosine kinases and tumor suppressors, and the extent to which mutations in each cooperate to direct oncogenic growth, is not well understood.The Ret RTK plays an essential role in both development and oncogenesis. During embryogenesis, Ret is required for development of the sympathetic and enteric nervous systems, the neural crest, and the excretory system (Schuchardt et al. 1994;Durbec et al. 1996;Enomoto et al. 2001). The extracellular portion of Ret contains cysteine repeats and a cadherinlike domain. The intracellular portion of Ret contains a tyrosine kinase catalytic domain and multiple tyrosine autophosphorylation sites. Four activating ligands have been identified: GDNF, Neurturin, Persephin, and Artemin all activate Ret through the GPI-linked co-

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Section: Genementioning

confidence: 99%

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confidence: 99%

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

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et al. 2005

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“…Acton and coworkers created tissue-specific transgenic mice expressing the human RET oncogene cDNA encoding the RET9 isoform in which the MEN2B-specific M918T mutation was introduced (Acton et al 2000). In humans, MEN2B was almost exclusively associated with the M918T alteration in exon 16 of RET gene.…”

Section: :1mentioning

confidence: 99%

“…In addition, M918T is the most frequent RET somatic point mutation observed in sporadic MTC (Romei et al 2016). Transgenic mice carrying human RET mutation developed bilateral MTC in three out of eight founder lines at 20-22 months of age and showed high CT levels (Acton et al 2000).…”

Section: :1mentioning

confidence: 99%

Animal models of medullary thyroid cancer: state of the art and view to the future

Mantovani

Gaudenzi

Circelli

et al. 2017

Endocrine-Related Cancer

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Medullary thyroid carcinoma is a neuroendocrine tumour originating from parafollicular C cells accounting for 5-10% of thyroid cancers. Increased understanding of diseasespecific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid carcinoma. These drugs increase progression-free survival; however, they are often poorly tolerated and most treatment responses are transient. Animal models are indispensable tools for investigating the pathogenesis, mechanisms for tumour invasion and metastasis and new therapeutic approaches for cancer. Unfortunately, only few models are available for medullary thyroid carcinoma. This review provides an overview of the state of the art of animal models in medullary thyroid carcinoma and highlights future developments in this field, with the aim of addressing salient features and clinical relevance. 24:1

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“…Crosstalk has been demonstrated between MET and RET at transcriptional and signaling levels, leading to the promotion of thyroid cell transformation and invasive phenotypes (30). The strong association of RET mutations and MET overexpression with thyroid malignancies combined with evidence of their oncogenic potential from preclinical models indicate that RET and MET may be important therapeutic targets (31)(32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer

Bentzien

Zuzow

Heald

et al. 2013

Thyroid

113

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Background: A limited number of approved therapeutic options are available to metastatic medullary thyroid cancer (MTC) patients, and the response to conventional chemotherapy and/or radiotherapy strategies is inadequate. Sporadic and inherited mutations in the tyrosine kinase RET result in oncogenic activation that is associated with the pathogenesis of MTC. Cabozantinib is a potent inhibitor of MET, RET, and vascular endothelial factor receptor 2 (VEGFR2), as well as other tyrosine kinases that have been implicated in tumor development and progression. The object of this study was to determine the in vitro biochemical and cellular inhibitory profile of cabozantinib against RET, and in vivo antitumor efficacy using a xenograft model of MTC. Methods: Cabozantinib was evaluated in biochemical and cell-based assays that determined the potency of the compound against wild type and activating mutant forms of RET. Additionally, the pharmacodynamic modulation of RET and MET and in vivo antitumor activity of cabozantinib was examined in a MTC tumor model following subchronic oral administration. Results: In biochemical assays, cabozantinib inhibited multiple forms of oncogenic RET kinase activity, including M918T and Y791F mutants. Additionally, it inhibited proliferation of TT tumor cells that harbor a C634W activating mutation of RET that is most often associated with MEN2A and familial MTC. In these same cells grown as xenograft tumors in nude mice, oral administration of cabozantinib resulted in dose-dependent tumor growth inhibition that correlated with a reduction in circulating plasma calcitonin levels. Moreover, immunohistochemical analyses of tumors revealed that cabozantinib reduced levels of phosphorylated MET and RET, and decreased tumor cellularity, proliferation, and vascularization. Conclusions: Cabozantinib is a potent inhibitor of RET and prevalent mutationally activated forms of RET known to be associated with MTC, and effectively inhibits the growth of a MTC tumor cell model in vitro and in vivo.

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Multiple endocrine neoplasia type 2B mutation in human RET oncogene induces medullary thyroid carcinoma in transgenic mice

Cited by 76 publications

References 20 publications

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

Animal models of medullary thyroid cancer: state of the art and view to the future

In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer

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