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Neutralizing a protein linked to tumor development

PLOS

In recent years, several proteins and various small synthetic chemicals have been designed to attack cancers by specifically inhibiting the activity of a class of enzymes that are often mutated in tumors - receptor tyrosine kinases. These receptors, which sit on the cell surface, normally stimulate intracellular pathways that control proliferation and other cellular functions in response to growth factors. In tumors, these receptors often have mutations that allow them to become active without growth factor binding, which results in the uncontrolled proliferation that is characteristic of cancer cells.

Reporting their work in the open-access journal PLoS Biology, Domenico Libri and colleagues now show that a class of molecules - called aptamers - may have potential as anticancer drugs. Aptamers - single-stranded nucleic acid molecules that are 50-100 bases long and can be selected for their ability to bind directly and tightly to specific proteins - are less likely to be targeted and destroyed by the body's natural defenses than some other types of potential therapeutic molecules.

Libri and colleagues chose to target a particular tyrosine kinase, RET, mutations of which cause multiple endocrine neoplasia (MEN) type 2 syndromes. Using a technique known as whole-cell SELEX (systematic evolution of ligands by exponential enrichment), a process in which large pools of oligonucleotides are enriched for molecules that can distinguish between a real and sham target, Libri and colleagues produced a sequence that not only bound RET but also blocked RET downstream signaling events and subsequent cellular and molecular changes. The researchers suggest that their method can be used to identify macromolecules with potential therapeutic effects against other transmembrane receptors involved in tumorigenesis.

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Citation: Cerchia L, Ducongé F, Pestourie C, Boulay J, Aissouni Y, et al. (2005) Neutralizing aptamers from whole-cell SELEX inhibit the RET receptor tyrosine kinase. PLoS Biol 3(4): e123.

CONTACT: Domenico Libri
Centre National de la Recherche Scientifique
CGM
Ave de la Terrasse
Gif sur Yvette, France 91190
+33-1-69-82-38-09
+33-1-69-82-38-77 (fax)
dominico.libri@cgm.cnrs-gif.fr

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