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 Medical oncology (Northwood, London, England)
Vol 25
Issue 2
Date 2008
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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
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, Jul 2018). Y
D820Y missense gain of function KIT D820Y lies within the protein kinase domain of the Kit protein (UniProt.org). D820Yresuts in constitutive phosphorylation of Kit and is transforming in cell culture (PMID: 19035443, PMID: 11984533), and has also been identified as a secondary mutation associated with imatinib-resistance (PMID: 18488160). Y
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), and has been identified as a secondary mutation associated with imatinib-resistance (PMID: 18488160). Y
Y553S missense unknown KIT Y553S lies within the juxtamembrane domain 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, Jul 2018). Y
H687Y missense unknown PDGFRA H687Y lies within the protein kinase domain of the Pdgfra protein (UniProt.org). H687Y has been identified as a secondary mutation and is potentially associated with drug resistance (PMID: 18488160), but has not been biochemically characterized and therefore, its effect on Pdgfra protein function is unknown (PubMed, Jul 2018). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT V555_L576del KIT D820G KIT D820Y gastrointestinal stromal tumor predicted - resistant Imatinib Clinical Study 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, who developed resistance to Gleevec (imatinib mesylate) (PMID: 18488160). 18488160
KIT A502_Y503dup KIT N822K gastrointestinal stromal tumor predicted - resistant Imatinib Clinical Study 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, who developed resistance to Gleevec (imatinib mesylate) (PMID: 18488160). 18488160
KIT V559A gastrointestinal stromal tumor predicted - resistant Imatinib Clinical Study 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 mesylate) (PMID: 18488160). 18488160
KIT A502_Y503dup PDGFRA H687Y gastrointestinal stromal tumor predicted - resistant Imatinib Clinical Study Actionable In a clinical study, PDGFRA H687Y was identified as a secondary mutation in a patient with gastrointestinal stromal tumor harboring primary KIT A502_Y503dup, who developed resistance to Gleevec (imatinib mesylate) (PMID: 18488160). 18488160
KIT V569_L576del KIT V654A KIT N822K gastrointestinal stromal tumor predicted - resistant Imatinib Clinical Study 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, who developed resistance to Gleevec (imatinib mesylate) (PMID: 18488160). 18488160
KIT Y553S KIT V556_T574del KIT D820Y gastrointestinal stromal tumor predicted - resistant Imatinib Clinical Study Actionable In a clinical study, KIT D820Y was identified as a secondary mutation in a patient with gastrointestinal stromal tumor harboring primary KIT V569_L576del and KIT Y553S mutations, who developed resistance to Gleevec (imatinib mesylate) (PMID: 18488160). 18488160
KIT W557_K558delinsCE KIT N822K gastrointestinal stromal tumor predicted - resistant Imatinib Clinical Study 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, who developed resistance to Gleevec (imatinib mesylate) (PMID: 18488160). 18488160
KIT K558_V560del KIT V654A gastrointestinal stromal tumor predicted - resistant Imatinib Clinical Study 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, who developed resistance to Gleevec (imatinib mesylate) (PMID: 18488160). 18488160