Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors

Carlomagno, Francesca; Guida, Teresa; Anaganti, Suresh; Vecchio, Giancarlo; Fusco, Alfredo; Ryan, Anderson J.; Billaud, Marc; Santoro, Massimo

doi:10.1038/sj.onc.1207810

Cited by 230 publications

(180 citation statements)

References 38 publications

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“…V804 corresponds to the gatekeeper residues of PDGFR, c-KIT, ABL, and EGFR kinases, and mutations at these residues result in resistance to various inhibitors [236]. These results suggest that RET V804L and V804M mutations in medullary carcinomas may show primary resistance to ZD6474 [235].…”

Section: Targeting Ret Mutations and Ret/ptcmentioning

confidence: 86%

“…ZD6474 was demonstrated to block phosphorylation and signaling from RET/PTC3 in vitro. In that way, the growth of human papillary carcinoma cell lines harboring RET/PTC1 and RET/PTC3-transformed fibroblasts was arrested in nude mice [234,235].…”

Section: Targeting Ret Mutations and Ret/ptcmentioning

confidence: 99%

“…In preclinical studies, it was shown that ZD6474 can inhibit all the mutated variants of RET except for the V804L and V804M mutations [235]. V804 corresponds to the gatekeeper residues of PDGFR, c-KIT, ABL, and EGFR kinases, and mutations at these residues result in resistance to various inhibitors [236].…”

Section: Targeting Ret Mutations and Ret/ptcmentioning

confidence: 99%

See 2 more Smart Citations

An update on molecular biology of thyroid cancers

Ömür

Baran

2014

Critical Reviews in Oncology/Hematology

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Section: Targeting Ret Mutations and Ret/ptcmentioning

confidence: 86%

Section: Targeting Ret Mutations and Ret/ptcmentioning

confidence: 99%

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An update on molecular biology of thyroid cancers

Ömür

Baran

2014

Critical Reviews in Oncology/Hematology

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“…However, the drug was not able to block RET when a hydrophobic amino-acid substitution occurs at V804, as in some inherited forms of MTC. 67 In a phase I trial in 77 patients with various solid carcinomas other than thyroid, doses up to 300 mg daily were tolerated with the most common dose-limiting side effects of diarrhea, hypertension, and skin rash. 68 On the basis of the preclinical demonstration that vandetanib inhibited most RET point mutations, a multicenter, open-label phase II trial studied the efficacy of the drug in patients with metastatic familial forms of MTC.…”

Section: Vandetanibmentioning

confidence: 99%

Targeted therapies for thyroid tumors

Sherman

2011

Modern Pathology

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Systemic chemotherapies for advanced or metastatic thyroid carcinomas have been of only limited effectiveness. For patients with differentiated or medullary carcinomas unresponsive to conventional treatments, novel therapies are needed to improve disease outcomes. Multiple novel therapies primarily targeting angiogenesis have entered clinical trials for metastatic thyroid carcinoma. Partial response rates up to 30% have been reported in single-agent studies, but prolonged disease stabilization is more commonly observed. The most successful agents target the vascular endothelial growth factor receptors, with potential targets including the mutant kinases associated with papillary and medullary oncogenesis. Two drugs approved for other malignancies, sorafenib and sunitinib, have had promising preliminary results reported, and are being used selectively for patients who do not qualify for clinical trials. At least one randomized, placebo-controlled phase III trial has been successfully completed, showing improved progression-free survival in patients with advanced or metastatic medullary thyroid carcinoma treated with vandetanib. Randomized trials for other agents are currently underway. Treatment for patients with metastatic or advanced thyroid carcinoma now emphasizes clinical trial opportunities for novel agents with considerable promise. Alternative options now exist for use of tyrosine kinase inhibitors that are well tolerated and may prove worthy of regulatory approval for this disease.

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“…Antibodies-As primary antibodies, we used rabbit polyclonal antisera to Erk2 (C-14) (Santa Cruz Biotechnology), phospho-MAPK (p42/ p44) (Cell Signaling), RET and phospho-RET (phospho-Tyr905) (11), and mouse monoclonal antibodies to enhanced green fluorescent protein, AU5, and HA epitopes (Berkeley Antibody Company), Src (Ab-1; Oncogene Science), c-Abl (Pharmingen), and phospho-tyrosine, PY (Santa Cruz Biotechnology and Upstate Biotechnology).…”

Section: Methodsmentioning

confidence: 99%

Activation of the Erk8 Mitogen-activated Protein (MAP) Kinase by RET/PTC3, a Constitutively Active Form of the RET Proto-oncogene

Iavarone

Acunzo

Carlomagno

et al. 2006

Journal of Biological Chemistry

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Mitogen-activated protein (MAP) kinases have a central role in several biological functions, including cell adhesion and spreading, chemotaxis, cell cycle progression, differentiation, and apoptosis. Extracellular signal-regulated kinase 8 (Erk8) is a large MAP kinase whose activity is controlled by serum and the c-Src non-receptor tyrosine kinase. Here, we show that RET/PTC3, an activated form of the RET proto-oncogene, was able to activate Erk8, and we demonstrate that such MAP kinase participated in RET/PTC3-dependent stimulation of the c-jun promoter. By using RET/PTC3 molecules mutated in specific tyrosine autophosphorylation sites, we characterized Tyr 981 , a known binding site for c-Src, as a major determinant of RET/PTC3-induced Erk8 activation, although, surprisingly, the underlying mechanism did not strictly depend on the activity of Src. In contrast, we present evidence that RET/PTC3 acts on Erk8 through Tyr 981 -mediated activation of c-Abl. Furthermore, we localized the region responsible for the modulation of Erk8 activity by the RET/PTC3 and Abl oncogenes in the Erk8 C-terminal domain. Altogether, these results support a role for Erk8 as a novel effector of RET/PTC3 and, therefore, RET biological functions. MAP3 kinases are a family of proline-directed serine/threonine kinases that play a central role in signal transduction in all eukaryotic cells, from yeast to humans (1). They coordinate signaling from a variety of extracellular and intracellular stimuli by acting as components of modular systems that involve other kinases and regulatory proteins. These stimuli induce specific phosphorylation on a conserved Thr-XaaTyr motif present in all MAP kinases, thereby inducing their activation. Consequently, these proteins transmit the signals to a vast array of cellular regulatory proteins including protein kinases, transcription factors, cytoskeletal proteins, and other enzymes (1).Erk8 is the last identified member of the MAP kinase family of proteins (2). Expressed in humans at high levels in the brain, kidney, and lung, its activity can be modulated by serum and c-Src (2). Although possessing a very typical MAP kinase domain, Erk8 also presents a peculiarly long C-terminal domain containing two putative SH3-binding sites (2). Information concerning its upstream activators, downstream effectors, and cellular functions is still extremely limited.RET is a typical trans-membrane receptor tyrosine-kinase, essential for the development of the sympathetic, parasympathetic, and enteric nervous system and of the kidney (3). In complex with four glycosylphosphatidylinositol-anchored coreceptors, GFR-␣ 1-4, the RET protein binds growth factors of the glial-derived neurotrophic factor family, mediating their intracellular signaling (4). As for other receptor tyrosine-kinases, ligand interaction triggers autophosphorylation of different RET intracellular tyrosine residues that work as docking sites for several adaptor and effector signaling molecules (5). Among such tyrosines, although Tyr 981 is a binding site...

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Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors

Cited by 230 publications

References 38 publications

An update on molecular biology of thyroid cancers

An update on molecular biology of thyroid cancers

Targeted therapies for thyroid tumors

Activation of the Erk8 Mitogen-activated Protein (MAP) Kinase by RET/PTC3, a Constitutively Active Form of the RET Proto-oncogene

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