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Selective KIT inhibitor KI-328 and HSP90 inhibitor show different potency against the type of KIT mutations recurrently identified in acute myeloid leukemia

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Abstract

Activating mutations of KIT play an important role in the pathophysiology of several human malignancies, including acute myeloid leukemia. Activated KIT kinase is therefore a promising molecular target for the treatment of many malignancies harboring KIT activation. Here we examined the potency of a novel KIT inhibitor KI-328 against different types of mutant KIT kinases recurrently identified in AML. KI-328 shows selective potency against KIT kinase for the in vitro kinase assay, and inhibits the growth of wild-type (Wt)- and mutant-KIT-expressing cells, while it has little potency against D816V-KIT. Comparable analysis of several potent KIT inhibitors regarding growth inhibitory effects on a variety of mutant-KIT-expressing cells revealed that multi-kinase inhibitors have the same potency against D816V-KIT as other mutant KITs; however, the predominant potency against D816V-KIT was observed in heat shock protein 90 (HSP90) inhibitors. Furthermore, HSP90 inhibitors suppress the growth of D816V-KIT-expressing cells at the concentration at which the growth of other mutant-KIT-expressing cells is not affected. These results collectively indicated that potent KIT inhibitors have different potency against the type of mutant KIT kinases. Therefore, KIT inhibitors are required to validate potency against several types of mutant KIT kinases for the clinical development.

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Acknowledgments

We would like to thank Ms. Manami Kira for secretarial assistance. This study was supported by Grants-in-Aid from the National Institute of Biomedical Innovation, the Ministry of Health, Labor and Welfare, the Scientific Research of the Ministry of Education, Culture, Sports, Science and Technology and the Global COE Program “Integrated Functional Molecular Medicine for Neuronal and Neoplastic Disorders” Japan.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Akane Tsujimura, Yuichi Ishikawa, Yumiko Mori & Tomoki Naoe

  2. Department of Infectious Diseases, Nagoya University School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya, 466-8560, Japan

    Akane Tsujimura, Hitoshi Kiyoi, Yuichi Ishikawa & Yumiko Mori

  3. Kyowa Hakko Kirin, Fuji Research Park, Shizuoka, Japan

    Yukimasa Shiotsu & Hiroshi Ishida

  4. Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    Tsutomu Toki & Etsuro Ito

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  1. Akane Tsujimura
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  2. Hitoshi Kiyoi
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  3. Yukimasa Shiotsu
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  4. Yuichi Ishikawa
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  6. Hiroshi Ishida
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  7. Tsutomu Toki
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  8. Etsuro Ito
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  9. Tomoki Naoe
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Correspondence to Hitoshi Kiyoi.

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Tsujimura, A., Kiyoi, H., Shiotsu, Y. et al. Selective KIT inhibitor KI-328 and HSP90 inhibitor show different potency against the type of KIT mutations recurrently identified in acute myeloid leukemia. Int J Hematol 92, 624–633 (2010). https://doi.org/10.1007/s12185-010-0692-8

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  • DOI: https://doi.org/10.1007/s12185-010-0692-8

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