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Double resistance to imatinib and AMG 706 caused by multiple acquired KIT exon 17 mutations in a gastrointestinal stromal tumour
  1. Florian Grabellus1,
  2. Peter Ebeling2,
  3. Karl Worm3,
  4. Sien-Yi Sheu3,
  5. Gerald Antoch4,
  6. Andrea Frilling5,*,
  7. Kurt W Schmid6,*
  1. 1Department of Pathology and Neuropathology, University Hospital of Essen, Essen, Germany
  2. 2Department of Internal Medicine (Cancer Research), University Hospital of Essen, Essen, Germany
  3. 3Department of Pathology and Neuropathology, University Hospital of Essen, Essen, Germany
  4. 4Department of Diagnostic and Interventional Radiology, University Hospital of Essen, Essen, Germany
  5. 5Department of General Surgery and Transplantation, University Hospital of Essen, Essen, Germany
  6. 6Department of Pathology and Neuropathology, University Hospital of Essen, Essen, Germany
  1. Correspondence to:
    Dr F Grabellus
    Department of Pathology and Neuropathology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany; florian.grabellus{at}uk-essen.de

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Gastrointestinal stromal tumours (GISTs) are rare mesenchymal neoplasms that arise in the wall of the gastrointestinal tract and originate from the interstitial cells of Cajal.1 The tumours are characterised by the expression of the receptor tyrosine kinase KIT (CD117, c-Kit). Activating mutations of the KIT proto-oncogene are known to be associated with the tumorigenesis of most GIST.2 The standard treatment for primary GIST is surgical resection, as GISTs are resistant to conventional chemotherapy. The multitargeted tyrosine-kinase inhibitor (MKI) imatinib mesylate (Glivec, Novartis, Basel, Switzerland) revolutionised the treatment for advanced disease. Although most patients benefit from imatinib, many subsequently develop acquired resistance.3 In patients developing resistance to imatinib, other MKIs provide clinical benefit. Sunitinib malate (Sutent, Pfizer, New York, USA) has demonstrated activity in patients with imatinib-resistant GIST,4 and other MKIs are currently in development, including AMG 706, an inhibitor of KIT, all vascular endothelial growth factor receptors and platelet-derived growth factor receptor. Preliminary data from recent clinical trials with AMG 706 showed an encouraging clinical benefit rate in patients with advanced high-dose imatinib-resistant GIST.5

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