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	Vol	Issue	Date	Pages	Journal Short Title
Endocrine-related cancer	16	1	2009 Mar	233-41	Endocr Relat Cancer

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

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
RET	E884K	missense	unknown	RET E884K lies within the protein kinase domain of the Ret protein (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, Feb 2024).
RET	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 (PMID: 10679286), and has also been demonstrated to occur as a secondary resistance mutation in conjunction with other RET mutations (PMID: 19029224).	Y
RET	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 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, Feb 2024).	Y

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 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
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