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Gut. 2007 July; 56(7): 1025–1026.
PMCID: PMC1994367

Double resistance to imatinib and AMG 706 caused by multiple acquired KIT exon 17 mutations in a gastrointestinal stromal tumour

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

We report on a 64‐year‐old woman with a 20 mm GIST of the small bowel (fig 1A1A,, table 11),), which was removed in September 2002.

figure gt115923.f1
Figure 1 (A) Histopathology of the high mitotic primary spindle cell type gastrointestinal stromal tumour (arrows: mitoses, H&E ×400). (B) KIT exon 17 point mutation c.2466T→A (G) found in three specimens of the imatinib/AMG ...
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Table 1 Tumour characteristics

In October 2003, peritoneal and liver metastases were recognised and treatment with imatinib (400 mg/day) was started, resulting in a complete metabolic response (on [18F] fluorodeoxyglucose positron emission tomography) 8 weeks later. Owing to the presence of a subsequent progressive mesenteric mass, the imatinib dose was increased (800 mg/day) in July 2004, leading to growth arrest. In April 2005 the lesion again showed slow progression, and additionally an adjacent nodule with increasing size appeared. In June 2005, AMG 706 therapy (125 mg/day) was started in a clinical trial, resulting in apparent growth arrest with tumour shrinkage (minor response) within the first 8 weeks, but after 3 months a radiological measurable increase in size occurred once again and both tumours started to fuse, subsequently presenting as a mass measuring 950 mm in January 2006, which was surgically removed because of small bowel obstruction. Additionally, multiple stable regressive peritoneal lesions were resected (table 11).). Because of delayed wound healing, AMG 706 therapy was interrupted 4 weeks after surgery. At 11 weeks after surgery, the wound was completely healed and imatinib (800 mg/day) was administered again, which resulted in a lack of tumour growth (no change) until August 2006. The subsequently observed progression of some liver lesions was treated by administration of sunitinib (50 mg/day for 4 weeks, then 2 weeks off).

Mutation analysis of KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 (table 11)) of the primary tumour, as well as from progressive and responding lesions, were carried out by PCR amplification (Primus 25 Thermocycler, MWG, Ebersberg, Germany) followed by direct sequencing of both forward and reverse strands with an ABI 3130 Genetic Analyzer (Applied Biosystems, Foster City, California, USA).

The primary tumour, as well as the regressive and progressive metastases, showed a deletion of 18 bp in exon 11 of KIT (c.1656_1673del18), resulting in loss of Tyr553 to Lys558. In addition, we found multiple secondary exon 17 point mutations of KIT in seven specimens of the peritoneal relapse. Three samples had one mutation (c.2466T→A or c.2466T→G) resulting in Asn822Lys (fig 1B1B).). The other four showed a combination of three mutations (c.2433T→C, c.2453A→G, and c.2467T→A or G). Although the first mentioned mutation represents a silent mutation, the others lead to Lys818Arg and Tyr823Asp, respectively (fig 1C1C).

Secondary KIT mutations are the most common cause of KIT‐dependent resistance. Point mutations of KIT exon 17 may occur in multiple form, and are found exclusively between aspartate‐816 and tyrosine‐823.6,7 The distal TK domain of KIT contains the kinase activation loop (A‐loop), a hinged region that must assume a particular conformation for full kinase activation. A‐loop mutations are generally resistant to imatinib, because of conformation changes resulting in an insufficient imatinib binding.3,8 The reported case suggests that exon 17 A‐loop mutations are responsible for imatinib resistance and also for resistance to AMG 706. The preliminary reported activity of AMG 706 in patients with imatinib‐resistant GIST5 may therefore be due to a response of tumours with secondary KIT mutations other than exon 17—for example, proximal TK domain mutations of KIT (exon 13 or 14).6 Hence, this patient might have benefited from a (combination) therapy with a more potent inhibitor of KIT activation loop mutants or by targeting downstream signalling molecules of KIT. Recently, Schittenhelm et al9 reported that dasatinib (BMS‐354825) has potent activity against KIT A‐loop mutations of GIST.

The complexity of imatinib resistance indicates the need for a precise understanding of the nature and timing of molecular events in resistant GIST. Detection of secondary KIT mutations may be the clue to guide and adapt individual second‐line therapies with alternative MKIs or agents against targets of KIT signalling.

Footnotes

*Member of the West German Cancer Center Essen (WTZE).

Competing interests: None.

References

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