Reference Detail

Ref Type

Journal Article

PMID

(18488160)

Authors

Lim KH, Huang MJ, Chen LT, Wang TE, Liu CL, Chang CS, Liu MC, Hsieh RK, Tzen CY

Title

Molecular analysis of secondary kinase mutations in imatinib-resistant gastrointestinal stromal tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Medical oncology (Northwood, London, England)	25	2	2008	207-13	Med Oncol

URL

Abstract Text

Most gastrointestinal stromal tumors (GISTs) are associated with activating kinase mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene, and imatinib has revolutionized the care of advanced GISTs. However, most patients gradually developed resistance to imatinib. We intend to identify the secondary kinase mutations in imatinib-resistant GISTs and to study the relationship between secondary kinase mutations and the clinical response to imatinib. Twelve advanced GIST patients, who have developed resistance to imatinib were included in this study. Paraffin-embedded pretreatment GIST specimens and progression lesions of the tumors after resistance to imatinib were analyzed for kinase mutations in exons 9, 11, 13, and 17 of KIT gene and exons of 10, 12, 14, and 18 of PDGFRA gene. Primary KIT mutations have been found in all but one of the primary tumors including one case harboring de novo double KIT exon 11 mutations. Secondary kinase mutations in KIT and PDGFRA were found in seven and 1 of 12 patients, respectively. Two patients harbored more than one secondary KIT mutations in different progression sites, and there are four types of clonal or polyclonal evolution being observed. The secondary PDGFRA exon 14 mutation H687Y is a novel mutation that has never been reported before. Acquired secondary kinase mutations are the most important cause of secondary imatinib resistance in advanced GISTs. The identification of secondary kinase mutations is important in the development of new therapeutic strategies.

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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	D820G	missense	unknown	KIT D820G lies within the protein kinase domain of the Kit protein (UniProt.org). D820G has been identified as a secondary mutation associated with imatinib resistance (PMID: 18488160), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2024).	Y
KIT	D820Y	missense	gain of function	KIT D820Y lies within the protein kinase domain of the Kit protein (UniProt.org). D820Y results in constitutive phosphorylation of Kit and is transforming in cell culture (PMID: 19035443, PMID: 11984533), and has also been identified as a secondary drug mutation associated with imatinib resistance (PMID: 18488160).	Y
KIT	N822K	missense	gain of function	KIT N822K lies within the activation loop in the protein kinase domain of the Kit protein (PMID: 24205792). N822K results in constitutive activation of Kit, increased Erk1/2 and Stat3 phosphorylation, is transforming in culture (PMID: 24205792, PMID: 31484543), leads to mislocalization of Kit to endolysosomes (PMID: 31484543), and has been identified as a secondary mutation associated with imatinib resistance (PMID: 18488160).	Y
KIT	Y553S	missense	unknown	KIT Y553S lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 16226710). Y553S has been identified as a secondary mutation associated with imatinib-resistance (PMID: 18488160), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT Y553S KIT W557_Q575del KIT D820Y	gastrointestinal stromal tumor	predicted - resistant	Imatinib	Case Reports/Case Series	Actionable	In a clinical study, KIT D820Y was identified as a secondary mutation in a patient with gastrointestinal stromal tumor harboring primary KIT W557_Q575del (reported as Q556_T574del) and KIT Y553S mutations, who developed resistance to Gleevec (imatinib) (PMID: 18488160).	18488160
KIT V555_L576del KIT D820G KIT D820Y	gastrointestinal stromal tumor	predicted - resistant	Imatinib	Case Reports/Case Series	Actionable	In a clinical study, KIT D820G and KIT D820Y were identified as secondary mutations in a patient with gastrointestinal stromal tumor harboring a primary KIT V555_L576del mutation, who developed resistance to Gleevec (imatinib) (PMID: 18488160).	18488160
KIT A502_Y503dup KIT N822K	gastrointestinal stromal tumor	predicted - resistant	Imatinib	Case Reports/Case Series	Actionable	In a clinical study, KIT N822K was identified as a secondary mutation in a patient with gastrointestinal stromal tumor harboring a primary KIT A502_Y503dup mutation, who developed resistance to Gleevec (imatinib) (PMID: 18488160).	18488160
KIT K558_V560del KIT V654A	gastrointestinal stromal tumor	predicted - resistant	Imatinib	Case Reports/Case Series	Actionable	In a clinical study, KIT V654A was identified as a secondary mutation in a patient with gastrointestinal stromal tumor harboring a primary KIT K558_V560del mutation, who developed resistance to Gleevec (imatinib) (PMID: 18488160).	18488160
KIT V559A	gastrointestinal stromal tumor	predicted - resistant	Imatinib	Case Reports/Case Series	Actionable	In a clinical study, KIT V559A was identified as a secondary mutation in a patient with gastrointestinal stromal tumor who developed resistance to Gleevec (imatinib) (PMID: 18488160).	18488160
KIT V569_L576del KIT V654A KIT N822K	gastrointestinal stromal tumor	predicted - resistant	Imatinib	Case Reports/Case Series	Actionable	In a clinical study, KIT V654A and KIT N822K were identified as secondary mutations in a patient with gastrointestinal stromal tumor harboring a primary KIT V569_L576del mutation, who developed resistance to Gleevec (imatinib) (PMID: 18488160).	18488160
KIT W557_K558delinsCE KIT N822K	gastrointestinal stromal tumor	predicted - resistant	Imatinib	Case Reports/Case Series	Actionable	In a clinical study, KIT N822K was identified as a secondary mutation in a patient with gastrointestinal stromal tumor harboring a primary KIT W557_K558delinsCE mutation, who developed resistance to Gleevec (imatinib mesylate) (PMID: 18488160).	18488160