Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate

Item Type:	Article
Title:	Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate
Creators Name:	Wardelmann, E. and Merkelbach-Bruse, S. and Pauls, K. and Thomas, N. and Schildhaus, H.U. and Heinicke, T. and Speidel, N. and Pietsch, T. and Buettner, R. and Pink, D. and Reichardt, P. and Hohenberger, P.
Abstract:	Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor α (PDGFRα) gene. Both PDGFRα and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.
Keywords:	Amino Acid Sequence, Amino Acid Sequence Homology, Base Sequence, Benzamides, DNA Mutational Analysis, Gastrointestinal Stromal Tumors, Molecular Sequence Data, Mutation, Piperazines, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-kit, Pyrimidines
Source:	Clinical Cancer Research
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Volume:	12
Page Range:	1743-1749
Date:	15 March 2006
Official Publication:	https://doi.org/10.1158/1078-0432.CCR-05-1211
PubMed:	View item in PubMed

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