Reference Detail

Ref Type

Journal Article

PMID

(15184865)

Authors

Carlomagno F, Guida T, Anaganti S, Vecchio G, Fusco A, Ryan AJ, Billaud M, Santoro M

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncogene	23	36	2004 Aug 12	6056-63	Oncogene

URL

Abstract Text

We have recently demonstrated that the pyrazolopyrimidines PP1 and PP2 and the 4-anilinoquinazoline ZD6474 display a strong inhibitory activity (IC(50)< or =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 IC(50): 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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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	L790F	missense	unknown	RET L790F lies within the protein kinase domain of the Ret protein (UniProt.org). L790F results in ligand-independent phosphorylation of Ret (PMID: 15184865, PMID: 23526464), however, also results in cell proliferation and transformation activity similar to wild-type Ret in cell culture (PMID: 21810974, PMID: 32546069), and therefore, its effect on Ret protein function is unknown.
RET	V804G	missense	unknown	RET V804G lies within the protein kinase domain of the Ret protein (UniProt.org). V804G in combination with C634R results in moderately decreased Ret kinase activity and transformation activity compared to C634R alone in cell culture (PMID: 15184865), but has not been characterized individually 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 M918T	Advanced Solid Tumor	sensitive	Vandetanib	Preclinical	Actionable	In a preclinical study, Caprelsa (vandetanib) inhibited Ret autophosphorylation and transforming activity in cells expressing RET M918T in culture (PMID: 15184865).	15184865
RET V804L	Advanced Solid Tumor	resistant	Vandetanib	Preclinical	Actionable	In a preclinical study, transformed cells expressing RET V804L demonstrated resistance to growth inhibition by Caprelsa (vandetanib) in culture (PMID: 15184865).	15184865
RET E768D	Advanced Solid Tumor	sensitive	Vandetanib	Preclinical	Actionable	In a preclinical study, Caprelsa (vandetanib) inhibited Ret autophosphorylation in transformed cells expressing RET E768D in culture (PMID: 15184865).	15184865
RET A883F	Advanced Solid Tumor	sensitive	Vandetanib	Preclinical	Actionable	In a preclinical study, Caprelsa (vandetanib) inhibited Ret autophosphorylation in transformed cells expressing RET A883F in culture (PMID: 15184865).	15184865
RET S891A	Advanced Solid Tumor	sensitive	Vandetanib	Preclinical	Actionable	In a preclinical study, Caprelsa (vandetanib) inhibited Ret autophosphorylation in transformed cells expressing RET S891A in culture (PMID: 15184865).	15184865
RET V804M	Advanced Solid Tumor	resistant	Vandetanib	Preclinical	Actionable	In a preclinical study, transformed cells expressing RET V804M demonstrated resistance to growth inhibition by Caprelsa (vandetanib) in culture (PMID: 15184865).	15184865
RET Y791F	Advanced Solid Tumor	sensitive	Vandetanib	Preclinical	Actionable	In a preclinical study, Caprelsa (vandetanib) inhibited Ret autophosphorylation in transformed cells expressing RET Y791F in culture (PMID: 15184865).	15184865
RET C634R RET V804G	Advanced Solid Tumor	sensitive	Vandetanib	Preclinical	Actionable	In a preclinical study, transformed cell lines expressing Ret protein carrying both C634R and V804G mutations were more sensitive to Vandetanib induced inhibition of Ret activity than cells expressing Ret C634R alone in culture (PMID: 15184865).	15184865
RET L790F	Advanced Solid Tumor	sensitive	Vandetanib	Preclinical	Actionable	In a preclinical study, Caprelsa (vandetanib) inhibited Ret autophosphorylation in transformed cells expressing RET L790F in culture (PMID: 15184865).	15184865
RET C634R	Advanced Solid Tumor	sensitive	Vandetanib	Preclinical	Actionable	In a preclinical study, Caprelsa (vandetanib) inhibited RET phosphorylation and decreased growth of transformed cells expressing RET C634R in culture (PMID: 15184865).	15184865