Reference Detail

Ref Type

Journal Article

PMID

(16954519)

Authors

Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ, Eisenberg BL, von Mehren M, Fletcher CD, Sandau K, McDougall K, Ou WB, Chen CJ, Fletcher JA

Title

Molecular correlates of imatinib resistance in gastrointestinal stromal tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology	24	29	2006 Oct 10	4764-74	J Clin Oncol

URL

Abstract Text

Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem.One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity.Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P = .002). Evidence for clonal evolution and/or polyclonal secondary kinase mutations was seen in three (18.8%) of 16 patients. Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical KIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways.Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. These findings have implications for future approaches to the growing problem of imatinib resistance in patients with advanced GISTs.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. 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 on a longer phrase with spaces (i.e. "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	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	C809G	missense	unknown	KIT C809G lies within the protein kinase domain of the Kit protein (UniProt.org). C809G has been associated with secondary resistance to select KIT inhibitors (PMID: 16954519), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Apr 2024).	Y
KIT	D820A	missense	gain of function - predicted	KIT D820A lies within the protein kinase domain of the Kit protein (UniProt.org). D820A has been demonstrated to occur as a secondary drug resistance mutation (PMID: 16954519, PMID: 31363162), and results in reduced Kit protein expression and stability, abnormal cellular localization, but constitutive Kit phosphorylation in the absence of Pkc in cell culture (PMID: 27440273), and therefore, is predicted to lead to a gain of Kit protein function.	Y
KIT	V560D	missense	gain of function	KIT V560D lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 19164557). V560D confers a gain of function to Kit, as indicated by constitutive phosphorylation of Kit in cell culture (PMID: 16954519, PMID: 20633291, PMID: 27440273) despite reduced expression, enhanced degradation, and cellular mislocalization (PMID: 27440273).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT V560D KIT D820A	gastrointestinal stromal tumor	resistant	Imatinib	Preclinical	Actionable	In a preclinical study, a gastrointestinal stromal tumor cell line harboring KIT V560D and KIT D820A demonstrated resistance to Gleevec (imatinib) in culture (PMID: 16954519).	16954519
KIT C809G	Advanced Solid Tumor	predicted - resistant	Imatinib	Preclinical - Cell culture	Actionable	In a preclinical study, KIT C809G was resistant to inhibition of phosphorylation by Gleevec (imatinib) in cultured cells (PMID: 16954519).	16954519
KIT V560D KIT D820A	gastrointestinal stromal tumor	resistant	Imatinib	Case Reports/Case Series	Actionable	In a clinical study, KIT D820A was identified as a secondary mutation in a patient with gastrointestinal stromal tumor harboring a primary KIT V560D mutation, who developed resistance to Gleevec (imatinib mesylate) (PMID: 16954519).	16954519
KIT K642E KIT C809G KIT N822H	gastrointestinal stromal tumor	predicted - resistant	Imatinib	Case Reports/Case Series	Actionable	In a clinical case study, an acquired KIT C809G mutation was identified in a gastrointestinal stromal tumor (GIST) patient harboring KIT K642E and KIT N822H at the time of progression on Gleevec (imatinib) (PMID: 16954519).	16954519