Identification of tyrosine 806 as a molecular determinant of RET kinase sensitivity to ZD6474
Carlomagno, F. and Guida, T. and Anaganti, S. and Provitera, L. and Kjaer, S. and McDonald, Neil Q. and Ryan, A.J. and Santoro, M. (2009) Identification of tyrosine 806 as a molecular determinant of RET kinase sensitivity to ZD6474. Endocrine-Related Cancer 16 (1), pp. 233-241. ISSN 1351-0088.
ZD6474 (vandetanib, Zactima, Astra Zeneca) is an anilinoquinazoline used to target the receptor tyrosine kinase RET in familial and sporadic thyroid carcinoma (IC50: 100 nM). The aim of this study was to identify molecular determinants of RET sensitivity to ZD6474. Here, we show that mutation of RET tyrosine 806 to cysteine (Y806C) induced RET kinase resistance to ZD6474 (IC50: 933 nM). Y806 maps close to the gate-keeper position at the RET kinase nucleotide-binding pocket. Although tyrosine 806 is a RET auto-phosphorylation site, its substitution to phenylalanine (Y806F) did not markedly affect RET susceptibility to ZD6474 (IC50: 87 nM), suggesting that phosphorylation of Y806 is not required for compound binding. Accordingly, the introduction of a phosphomimetic residue (Y806E) also caused resistance to ZD6474, albeit of a lesser degree (IC50: 512 nM) than the cysteine mutation. Y806C/E RET mutants were also resistant to ZD6474 with respect to intracellular signalling and activation of an AP1-responsive promoter. We conclude that Y806 is a molecular determinant of RET sensitivity to ZD6474. Y806C is a natural RET mutation identified in a patient affected by multiple endocrine neoplasia type 2B. Based on its rare occurrence, it is unlikely that Y806C will be a frequent cause of refractoriness to ZD6474; however, it may be envisaged that mutations at this site can mediate secondary resistance formation in patients treated with the compound.
|School:||Birkbeck Schools and Departments > School of Science > Biological Sciences|
|Research Centre:||Structural Molecular Biology, Institute of (ISMB)|
|Date Deposited:||04 Aug 2010 14:09|
|Last Modified:||06 Dec 2016 10:43|
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