Document Detail


Molecular correlates of imatinib resistance in gastrointestinal stromal tumors.
MedLine Citation:
PMID:  16954519     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Authors:
Michael C Heinrich; Christopher L Corless; Charles D Blanke; George D Demetri; Heikki Joensuu; Peter J Roberts; Burton L Eisenberg; Margaret von Mehren; Christopher D M Fletcher; Katrin Sandau; Karen McDougall; Wen-bin Ou; Chang-Jie Chen; Jonathan A Fletcher
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Publication Detail:
Type:  Clinical Trial, Phase II; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2006-09-05
Journal Detail:
Title:  Journal of clinical oncology : official journal of the American Society of Clinical Oncology     Volume:  24     ISSN:  1527-7755     ISO Abbreviation:  J. Clin. Oncol.     Publication Date:  2006 Oct 
Date Detail:
Created Date:  2006-10-09     Completed Date:  2006-10-30     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8309333     Medline TA:  J Clin Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4764-74     Citation Subset:  IM    
Affiliation:
Division of Hematology/Oncology, Department of Pathology, Oregon Health & Science University Cancer Institute, Oregon Health & Science University, Portland, OR, USA. Heinrich@ohsu.edu
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Cohort Studies
Drug Resistance, Neoplasm / genetics*
Gastrointestinal Stromal Tumors / drug therapy*,  genetics*
Humans
Piperazines / pharmacology*
Platelet-Derived Growth Factor / genetics
Proto-Oncogene Proteins c-kit / genetics
Pyrimidines / pharmacology*
RNA Interference
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Piperazines; 0/Platelet-Derived Growth Factor; 0/Pyrimidines; 0/platelet-derived growth factor A; 152459-95-5/imatinib; EC 2.7.10.1/Proto-Oncogene Proteins c-kit
Comments/Corrections
Comment In:
J Clin Oncol. 2007 Mar 20;25(9):1146-7; author reply 1147-8   [PMID:  17369583 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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