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Inactivity of imatinib in gastrointestinal stromal tumors (GISTs) harboring a KIT activation-loop domain mutation (exon 17 mutation pN822K).

Spitaleri G, Biffi R, Barberis M, Fumagalli C, Toffalorio F, Catania C, Noberasco C, Lazzari C, de Marinis F, De Pas T - Onco Targets Ther (2015)

Bottom Line: Beyond these, there are many other mutations that are considered rare and are associated with unknown clinical behavior.In the literature, there are poor and inconsistent data about the inhibitor sensitivity of mutations occurring in the activation-loop domain encoded by exon 17.A review of the literature is also presented.

View Article: PubMed Central - PubMed

Affiliation: Division of Chest Medical Oncology, Rare Tumors and Sarcomas, European Institute of Oncology, Milan, Italy.

ABSTRACT
The development of gastrointestinal stromal tumors (GISTs) is largely driven by mutations in the KIT and PDGFRα genes. Imatinib mesylate is an oral small molecular tyrosine kinase inhibitor that mainly targets abl, c-KIT, and PDGFRα. Imatinib achieves disease control in approximately 70%-85% of patients with advanced GIST, and the median progression-free survival is 20-24 months. The efficacy of imatinib correlates with tumor kinase mutational status (exon 11 mutations mainly), and some mutations are known to be responsible for primary and secondary imatinib resistance. Beyond these, there are many other mutations that are considered rare and are associated with unknown clinical behavior. In the literature, there are poor and inconsistent data about the inhibitor sensitivity of mutations occurring in the activation-loop domain encoded by exon 17. In this article, we focus on a case of a patient suffering from GIST, harboring an extremely rare KIT activation-loop domain mutation (exon 17 mutation pN822K) treated with imatinib. A review of the literature is also presented.

No MeSH data available.


Related in: MedlinePlus

Electropherogram obtained by bidirectional Sanger sequencing of two independent amplifications, both showing a pN822K mutation.
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f3-ott-8-1997: Electropherogram obtained by bidirectional Sanger sequencing of two independent amplifications, both showing a pN822K mutation.

Mentions: Macroscopically, the tumor was roundish and with a hard consistency; the maximum diameter was 8.5 cm. The cut surface was grayish and dishomogeneous for the presence of hemorrhagic areas. Histologically, the tumor was composed of bland spindle cells (Figures 1 and 2A). There were no areas of tumor necrosis. Many dilated and thrombosed vessels resembling similar findings seen in neurogenic tumors were intermingled within the tumor cells. Immunocytochemical stains revealed strong cytoplasmic expression of CD117, DOG1, and CD34 (Figure 2B and C). No expression was detected for desmin and S100 protein. c-KIT (exons 9, 11, 13, and 17) and PDGFRα (exons 12, 14, and 18) mutational analyses were performed by bidirectional Sanger sequencing, using BigDye Terminator chemistry, on a 3500 Dx Genetic Analyzer. The test results showed a single mutation in exon 17 of the c-KIT gene (pN822K; Figure 3), confirmed in two independent amplifications, while the PDGFRα mutational status was wild type. Based on the evidence of prior response to imatinib (no tumor shrinkage at instrumental evaluation and no pathological response at the histological report) and the evidence of this rare mutation, treatment with imatinib was not restarted and we decided to begin a clinical–instrumental follow-up every 3–4 months.


Inactivity of imatinib in gastrointestinal stromal tumors (GISTs) harboring a KIT activation-loop domain mutation (exon 17 mutation pN822K).

Spitaleri G, Biffi R, Barberis M, Fumagalli C, Toffalorio F, Catania C, Noberasco C, Lazzari C, de Marinis F, De Pas T - Onco Targets Ther (2015)

Electropherogram obtained by bidirectional Sanger sequencing of two independent amplifications, both showing a pN822K mutation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4548749&req=5

f3-ott-8-1997: Electropherogram obtained by bidirectional Sanger sequencing of two independent amplifications, both showing a pN822K mutation.
Mentions: Macroscopically, the tumor was roundish and with a hard consistency; the maximum diameter was 8.5 cm. The cut surface was grayish and dishomogeneous for the presence of hemorrhagic areas. Histologically, the tumor was composed of bland spindle cells (Figures 1 and 2A). There were no areas of tumor necrosis. Many dilated and thrombosed vessels resembling similar findings seen in neurogenic tumors were intermingled within the tumor cells. Immunocytochemical stains revealed strong cytoplasmic expression of CD117, DOG1, and CD34 (Figure 2B and C). No expression was detected for desmin and S100 protein. c-KIT (exons 9, 11, 13, and 17) and PDGFRα (exons 12, 14, and 18) mutational analyses were performed by bidirectional Sanger sequencing, using BigDye Terminator chemistry, on a 3500 Dx Genetic Analyzer. The test results showed a single mutation in exon 17 of the c-KIT gene (pN822K; Figure 3), confirmed in two independent amplifications, while the PDGFRα mutational status was wild type. Based on the evidence of prior response to imatinib (no tumor shrinkage at instrumental evaluation and no pathological response at the histological report) and the evidence of this rare mutation, treatment with imatinib was not restarted and we decided to begin a clinical–instrumental follow-up every 3–4 months.

Bottom Line: Beyond these, there are many other mutations that are considered rare and are associated with unknown clinical behavior.In the literature, there are poor and inconsistent data about the inhibitor sensitivity of mutations occurring in the activation-loop domain encoded by exon 17.A review of the literature is also presented.

View Article: PubMed Central - PubMed

Affiliation: Division of Chest Medical Oncology, Rare Tumors and Sarcomas, European Institute of Oncology, Milan, Italy.

ABSTRACT
The development of gastrointestinal stromal tumors (GISTs) is largely driven by mutations in the KIT and PDGFRα genes. Imatinib mesylate is an oral small molecular tyrosine kinase inhibitor that mainly targets abl, c-KIT, and PDGFRα. Imatinib achieves disease control in approximately 70%-85% of patients with advanced GIST, and the median progression-free survival is 20-24 months. The efficacy of imatinib correlates with tumor kinase mutational status (exon 11 mutations mainly), and some mutations are known to be responsible for primary and secondary imatinib resistance. Beyond these, there are many other mutations that are considered rare and are associated with unknown clinical behavior. In the literature, there are poor and inconsistent data about the inhibitor sensitivity of mutations occurring in the activation-loop domain encoded by exon 17. In this article, we focus on a case of a patient suffering from GIST, harboring an extremely rare KIT activation-loop domain mutation (exon 17 mutation pN822K) treated with imatinib. A review of the literature is also presented.

No MeSH data available.


Related in: MedlinePlus