Molecular correlates of imatinib resistance in gastrointestinal stromal tumors

Michael Heinrich, Christopher Corless, Charles 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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)4764-4774
Number of pages11
JournalJournal of Clinical Oncology
Volume24
Issue number29
DOIs
StatePublished - Oct 10 2006
Externally publishedYes

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Gastrointestinal Stromal Tumors
Phosphotransferases
Mutation
Platelet-Derived Growth Factor
Imatinib Mesylate
Clonal Evolution
Stromal Cells
RNA Interference
Exons
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. / Heinrich, Michael; Corless, Christopher; Blanke, Charles; Demetri, George D.; Joensuu, Heikki; Roberts, Peter J.; Eisenberg, Burton L.; Von Mehren, Margaret; Fletcher, Christopher D M; Sandau, Katrin; McDougall, Karen; Ou, Wen Bin; Chen, Chang Jie; Fletcher, Jonathan A.

In: Journal of Clinical Oncology, Vol. 24, No. 29, 10.10.2006, p. 4764-4774.

Research output: Contribution to journalArticle

Heinrich, M, Corless, C, Blanke, C, Demetri, GD, Joensuu, H, Roberts, PJ, Eisenberg, BL, Von Mehren, M, Fletcher, CDM, Sandau, K, McDougall, K, Ou, WB, Chen, CJ & Fletcher, JA 2006, 'Molecular correlates of imatinib resistance in gastrointestinal stromal tumors', Journal of Clinical Oncology, vol. 24, no. 29, pp. 4764-4774. https://doi.org/10.1200/JCO.2006.06.2265
Heinrich, Michael ; Corless, Christopher ; Blanke, Charles ; Demetri, George D. ; Joensuu, Heikki ; Roberts, Peter J. ; Eisenberg, Burton L. ; Von Mehren, Margaret ; Fletcher, Christopher D M ; Sandau, Katrin ; McDougall, Karen ; Ou, Wen Bin ; Chen, Chang Jie ; Fletcher, Jonathan A. / Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. In: Journal of Clinical Oncology. 2006 ; Vol. 24, No. 29. pp. 4764-4774.
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abstract = "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.",
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T1 - Molecular correlates of imatinib resistance in gastrointestinal stromal tumors

AU - Heinrich, Michael

AU - Corless, Christopher

AU - Blanke, Charles

AU - Demetri, George D.

AU - Joensuu, Heikki

AU - Roberts, Peter J.

AU - Eisenberg, Burton L.

AU - Von Mehren, Margaret

AU - Fletcher, Christopher D M

AU - Sandau, Katrin

AU - McDougall, Karen

AU - Ou, Wen Bin

AU - Chen, Chang Jie

AU - Fletcher, Jonathan A.

PY - 2006/10/10

Y1 - 2006/10/10

N2 - 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.

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