Antitumor Capacity of a Dominant-Negative<i>RET</i>Proto-Oncogene Mutant in a Medullary Thyroid Carcinoma Model

Drosten, Matthias; Stiewe, Thorsten; Pützer, Brigitte M.

doi:10.1089/104303403766682232

Cited by 40 publications

(22 citation statements)

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“…Molecular mimicry has been shown using in vitro models to inhibit constitutively active RET [50]. Dominant negative RET mutants may have a future role in the treatment of MTC: these mutant proteins can dimerize with oncogenic RET molecules, resulting in the retention of the protein complex in the endoplasmic reticulum, blocking transduction and/or ultimately leading to increased apoptosis [51].…”

Section: Ongoing Challenges and Unmet Needsmentioning

confidence: 99%

RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

Lodish¹,

Stratakis²

2008

Expert Review of Anticancer Therapy

105

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SummaryHereditary medullary thyroid carcinoma (MTC) is caused by specific autosomal dominant gain-of function mutations in the RET proto-oncogene. Genotype-phenotype correlations exist that help predict the presence of other associated endocrine neoplasms as well as the timing of thyroid cancer development. MTC represents a promising model for targeted cancer therapy, as the oncogenic event responsible for initiating malignancy has been well characterized. The RET proto-oncogene has become the rational target for molecularly designed drug therapy. Tyrosine kinase inhibitors targeting activated RET are currently in clinical trials for the treatment of patients with MTC. This review will provide a brief overview of MTC and the associated RET oncogenic mutations, as well as a summary of the therapies designed to strategically interfere with pathologic activation of the RET oncogene. KeywordsMultiple endocrine neoplasia; tyrosine kinase inhibitors; thyroid cancer; oncogenes; clinical trial Introductory overview of the disease: epidemiology and pathophysiologyThyroid cancer represents approximately 1% of malignancies occurring in the United States, accounting for an estimated 33,550 cancer diagnoses and 1,530 cancer deaths per year. Of these cancers, 2% to 3% are due to medullary thyroid cancer (MTC) [1]. MTC is a rare calcitoninproducing tumor that arises from the thyroid gland parafollicular C cells, which are derived from the embryonic neural crest. While the majority of patients with MTC have sporadic disease, 25% to 30% of cases are due to hereditary forms of MTC [2]. The presentation of disease in hereditary MTC is usually bilateral and multicentric, compared with a single, unilateral thyroid tumor found in sporadic cases [3].Hereditary MTC is classified according to three distinct clinical subtypes (Table 1 Summary of current optimal therapeutic practicesMTC is relatively unresponsive to radiation therapy and to standard chemotherapeutic regimens [8,9]. Various chemotherapeutic regimens, including alkylating agents, antimetabolites, and anthracyclines have shown no proven benefit in patients with metastatic MTC [10][11][12]. Radiation therapy has only a palliative role in the treatment of MTC [13]. Surgery remains the only standard treatment for patients with MTC: total thyroidectomy that is performed before MTC grows or spreads beyond the gland is currently the only curative therapy.Once MTC metastasizes, it has a tendency to spread to local and regional lymph nodes, and more distantly to lung, liver, and bone [8]. Although MTC is often widely metastatic, it tends to be a slow growing tumor. Patients with metastatic disease continue to have 5 and 10 year survival rates of 80% and 70%, respectively [14]. However, and despite its slow growth, the average survival for MTC is lower than that for other more common types of thyroid cancer, such as papillary and follicular carcinoma which have a 90% to 94% 5-year survival rate, respectively [15]. Decreased survival in MTC can be correlated with the stage of diagnos...

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Section: Ongoing Challenges and Unmet Needsmentioning

confidence: 99%

RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

Lodish¹,

Stratakis²

2008

Expert Review of Anticancer Therapy

105

View full text Add to dashboard Cite

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“…Evidence for its suitability as a target comes from suppression of oncogenic RET in a thyroid carcinoma model system by small molecule inhibition (35) as well as from the beneficial effect of a dominant-negative RET mutant in MTC cells blocking tumor growth (36). Small molecule inhibitors of protein kinases have already been proven clinically useful for a variety of human diseases (37,38).…”

mentioning

confidence: 99%

Structure and Chemical Inhibition of the RET Tyrosine Kinase Domain

Knowles

Murray‐Rust

Kjær

et al. 2006

Journal of Biological Chemistry

252

255

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The RET proto-oncogene encodes a receptor tyrosine kinase for the glial cell line-derived neurotrophic factor family of ligands. Loss-of-function mutations in RET are implicated in Hirschsprung disease, whereas activating mutations in RET are found in human cancers, including familial medullar thyroid carcinoma and multiple endocrine neoplasias 2A and 2B. We report here the biochemical characterization of the human RET tyrosine kinase domain and the structure determination of the non-phosphorylated and phosphorylated forms. Both structures adopt the same active kinase conformation competent to bind ATP and substrate and have a pre-organized activation loop conformation that is independent of phosphorylation status. In agreement with the structural data, enzyme kinetic data show that autophosphorylation produces only a modest increase in activity. Longer forms of RET containing the juxtamembrane domain and C-terminal tail exhibited similar kinetic behavior, implying that there is no cis-inhibitory mechanism within the RET intracellular domain. Our results suggest the existence of alternative inhibitory mechanisms, possibly in trans, for the autoregulation of RET kinase activity. We also present the structures of the RET tyrosine kinase domain bound to two inhibitors, the pyrazolopyrimidine PP1 and the clinically relevant 4-anilinoquinazoline ZD6474. These structures explain why certain multiple endocrine neoplasia 2-associated RET mutants found in patients are resistant to inhibition and form the basis for design of more effective inhibitors.The RET (rearranged during transfection) gene was originally isolated as an oncogenic fusion protein in cell transformation assays (1). The RET proto-oncogene (2), on human chromosome 10q11.2, encodes a receptor tyrosine kinase (RTK) 4 (3-5) activated by members of the glial cell line-derived neurotrophic factor (GDNF) ligand family (GDNF, neurturin, artemin, and persephin) (6) in conjunction with a ligand-specific coreceptor (GFR␣1-4) (7). RET signaling is essential for development, survival, and regeneration of many neuronal populations such as those in the enteric and sympathetic nervous systems (6) and the kidney (8, 9). The domain organization of RET is shown in Fig. 1A; orthologs exist from Drosophila to human and share a high degree of sequence similarity (90% in vertebrates) throughout the cytoplasmic domain and, to a lesser extent, within the extracellular region.GDNF family ligands do not interact directly with RET; instead, signaling via RET depends on formation of a tripartite complex of RET, a GDNF family ligand, and its cognate glycosylphosphatidylinositol-linked GFR␣ (10, 11). In addition, ligand binding requires Ca 2ϩ ions chelated to the RET extracellular domain (12, 13). According to the classical RTK paradigm, formation of the complex promotes RET dimerization, leading to trans-autophosphorylation within the RET intracellular domain (RET-ICD). There are two tyrosine residues (Tyr 900 and Tyr 905 ) in the RET tyrosine kinase domain (RET-KD) activation loop (...

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“…Drosten et al [91] reported that adenovirus-mediated transduction of dominant negative RET into TT cells reduced expression of oncogenic RET receptors on the cell surface. They also reported that inoculation of dominant negative RET-expressing MTC cells into nude mice led to an almost complete suppression of tumor growth [91,92]. These results suggest that inhibition of oncogenic RET expression by a dominantnegative RET mutant is an effective approach for MTC treatment, although many issues remain to be resolved before viral vectors can be used in vivo.…”

Section: Other Strategies To Inhibit Retmentioning

confidence: 97%

Medullary Thyroid Cancer: A Promising Model for Targeted Therapy

Torino¹,

Paragliola

Barnabei³

et al. 2010

CMM

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Abstract:In recent years, the clinical validation of molecular targeted therapies inhibiting the action of pathogenic tyrosine kinase (TK) has been one of the most exciting developments in cancer research. In this context, medullary thyroid carcinoma (MTC) represents a promising model. It is well known that in MTC, the RET receptor TK and its signal transduction pathways, lead to subsequent neoplastic transformation. Several strategies aimed at blocking the activation and signaling of RET have been preclinically tested. The most advanced results have been obtained by competitive inhibition of RET-TK activity by tyrosine kinases inhibitors (TKI). However, although the inhibition of the RET pathway is actually one of the most studied for therapeutic purposes, other signal transduction pathways have been recognized to contribute to the growth and functional activity of MTC and are considered attractive therapeutic targets.To date, surgery represents the only curative treatment of MTC. Despite promising initial results, studies on targeted agents are in early stages and several issues regarding preclinical evaluations and clinical trials of new targeted agents in MTC are still unresolved. Now, available mouse models bearing mutations of RET or other genes, which spontaneously develop MTC, promise to improve preclinical evaluation of activity of targeted compounds. Furthermore, the rarity of the disease and the number of patients available for enrolment may lessen the relevance of clinical trials. A major effort needs to be made by endocrinologists and oncologists to refer their patients for multi-institutional trials in order to optimize them, perform translational studies and expedite the availability of novel beneficial selective therapies.

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Antitumor Capacity of a Dominant-NegativeRETProto-Oncogene Mutant in a Medullary Thyroid Carcinoma Model

Cited by 40 publications

References 61 publications

RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

Structure and Chemical Inhibition of the RET Tyrosine Kinase Domain

Medullary Thyroid Cancer: A Promising Model for Targeted Therapy

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