Reference Detail

Ref Type Journal Article
PMID (19029224)
Authors Carlomagno F, Guida T, Anaganti S, Provitera L, Kjaer S, McDonald NQ, Ryan AJ, Santoro M
Title Identification of tyrosine 806 as a molecular determinant of RET kinase sensitivity to ZD6474.
Journal Endocrine-related cancer
Vol 16
Issue 1
Date 2009 Mar
URL
Abstract Text ZD6474 (vandetanib, Zactima, Astra Zeneca) is an anilinoquinazoline used to target the receptor tyrosine kinase RET in familial and sporadic thyroid carcinoma (IC(50): 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 (IC(50): 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 (IC(50): 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 (IC(50): 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
E884K missense unknown RET E884K lies within the protein kinase domain and substrate recognition region of the Ret protein (PMID: 10622534, UniProt.org). E884K has been identified in the scientific literature (PMID: 10622534, PMID: 19029224, PMID: 28351340), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2019).
Y806C missense gain of function - predicted RET Y806C lies within the protein kinase domain of the Ret protein (UniProt.org). Y806C is predicted to lead to a gain of Ret protein function as indicated by transformation of cultured cells in one study (PMID: 10679286), and has also been demonstrated to occur as a secondary resistance mutation in conjunction with other RET mutations (PMID: 19029224). Y
Y806E missense unknown RET Y806E lies within the protein kinase domain of the Ret protein (UniProt.org). Y806E has been demonstrated to confer secondary drug resistance mutation in the context of other RET activating mutations (PMID: 19029224), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2019). Y
Y806F missense unknown RET Y806F lies within the protein kinase domain of the Ret protein (UniProt.org). Y806F does not alter drug sensitivity in the context of other RET activating mutations (PMID: 19029224), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET C634R RET V804M Advanced Solid Tumor resistant Vandetanib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells co-expressing RET C634R and RET V804M were resistant to treatment with Caprelsa (vandetanib) in culture (PMID: 19029224). 19029224
RET C634R RET Y806C Advanced Solid Tumor resistant Vandetanib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells co-expressing RET C634R and RET Y806C were resistant to treatment with Caprelsa (vandetanib) in culture (PMID: 19029224). 19029224
RET C634R RET Y806F Advanced Solid Tumor predicted - sensitive Vandetanib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells co-expressing RET C634R and RET Y806F in culture demonstrated inhibition of Ret phosphorylation and activity in kinase assays when treated with Caprelsa (vandetanib) (PMID: 19029224). 19029224
RET C634R RET Y806E Advanced Solid Tumor resistant Vandetanib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells co-expressing RET C634R and RET Y806E were resistant to treatment with Caprelsa (vandetanib) in culture (PMID: 19029224). 19029224