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

Oncogene volume 23, pages 6056–6063 (2004)Cite this article

Abstract

We have recently demonstrated that the pyrazolopyrimidines PP1 and PP2 and the 4-anilinoquinazoline ZD6474 display a strong inhibitory activity (IC50⩽100 nM) towards constitutively active oncogenic RET kinases. Here, we show that most oncogenic MEN2-associated RET kinase mutants are highly susceptible to PP1, PP2 and ZD6474 inhibition. In contrast, MEN2-associated swap of bulky hydrophobic leucine or methionine residues for valine 804 in the RET kinase domain causes resistance to the three compounds. Substitution of valine 804 with the small amino- acid glycine renders the RET kinase even more susceptible to inhibition (ZD6474 IC50: 20 nM) than the wild-type kinase. Our data identify valine 804 of RET as a structural determinant mediating resistance to pyrazolopyrimidines and 4-anilinoquinazolines.

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Acknowledgements

We are grateful to Fortunato Ciardiello and Giampaolo Tortora for helpful discussions. This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), the Progetto Strategico Oncologia of the CNR/MIUR, the Italian Ministero per l’Istruzione, Università e Ricerca Scientifica (MIUR) and grants of the Italian Ministero della Salute.

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Authors and Affiliations

  1. Dipartimento di Biologia e Patologia Cellulare e Molecolare, University ‘Federico II’, c/o Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, via S. Pansini 5, Napoli, Italia

    Francesca Carlomagno, Teresa Guida, Suresh Anaganti, Giancarlo Vecchio, Alfredo Fusco & Massimo Santoro

  2. Cancer Discovery, Astra Zeneca Mereside, Alderley Park, Macclesfield, Cheshire, UK

    Anderson J Ryan

  3. Laboratoire de Genetique, CNRS, Lyon, France

    Marc Billaud

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  1. Francesca Carlomagno
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  2. Teresa Guida
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Correspondence to Massimo Santoro.

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Carlomagno, F., Guida, T., Anaganti, S. et al. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene 23, 6056–6063 (2004). https://doi.org/10.1038/sj.onc.1207810

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