Reference Detail

Ref Type

Journal Article

PMID

(15236194)

Authors

Tamborini E, Bonadiman L, Greco A, Albertini V, Negri T, Gronchi A, Bertulli R, Colecchia M, Casali PG, Pierotti MA, Pilotti S

Title

A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Gastroenterology	127	1	2004 Jul	294-9	Gastroenterology

URL

Abstract Text

Imatinib, a tyrosine kinase inhibitor of BCR-ABL, KIT, and platelet-derived growth factor receptor, is used in patients with chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). Primary and acquired resistance to the drug can occur in both diseases. Molecular mechanisms have been reported in CML and GIST for primary resistance, whereas extensive studies on the mechanisms responsible for secondary resistance have been almost exclusively reported for CML.In a patient with advanced GIST undergoing imatinib therapy, an isolated progressing peritoneal mass was excised, along with 2 still-responding lesions. Complementary DNA and genomic DNA were analyzed by sequencing for c-Kit gene mutations. KIT receptor expression and phosphorylation status were assessed by immunoprecipitation and Western blot. Transient-transfection experiments were performed with mutagenized KIT constructs, and their activation status was assessed.In addition to an exon 11 mutation, shared among all of the analyzed lesions, a novel point mutation in c-Kit exon 14 resulting in T670I substitution was found only in the progressing lesion, which harbored a phosphorylated receptor, as opposed to the finding of an inactive receptor in responding lesions. Functional analyses showed that KIT/T670I is insensitive to imatinib and that T670I mutation, introduced in a receptor responding to imatinib, subverted its sensitivity to the drug.This new mutation was confined to the progressing lesion; the resulting amino acidic substitution, T670I, affecting the ATP/imatinib pocket of KIT, makes it insensitive to the drug. Interestingly, this substitution is a homologue to the T315I mutation already reported in CML, where it is responsible for acquired resistance to imatinib.

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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
KIT	T670I	missense	gain of function	KIT T670I lies within the ATP pocket in the protein kinase domain of the Kit protein (PMID: 15236194, PMID: 22355224). T670I confers a gain of function on Kit as indicated by constitutive Kit phosphorylation, is transforming in cultured cells, and is associated with resistance to Kit inhibitors (PMID: 17699867, PMID: 15236194).	Y
KIT	V560del	deletion	gain of function	KIT V560del (also reported as V559del) results in the deletion of an amino acid in the juxtamembrane domain (exon 11) of the Kit protein at amino acid 560 (PMID: 12879016). V560del confers a gain of function to Kit, resulting in constitutive, ligand independent phosphorylation of Kit and activation of Akt in cell culture (PMID: 15236194, PMID: 22282465), and transformation of cultured cells (PMID: 19861435).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT T670I	gastrointestinal stromal tumor	predicted - resistant	Imatinib	Case Reports/Case Series	Actionable	In a clinical case report, a patient with a gastrointestinal stromal tumor developed disease progression while being treated with Gleevec (imatinib), demonstrating a KIT T670I mutation in the progressive lesion (PMID: 15236194).	15236194