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Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma

Nguyen, Tran B., Sakata-Yanagimoto, Mamiko, Fujisawa, Manabu, Nuhat, Sharna Tanzima, Miyoshi, Hiroaki, Nannya, Yasuhito, Hashimoto, Koichi, Fukumoto, Kota, Bernard, Olivier A., Kiyoki, Yusuke, Ishitsuka, Kantaro, Momose, Haruka, Sukegawa, Shinichiro, Shinagawa, Atsushi, Suyama, Takuya, Sato, Yuji, Nishikii, Hidekazu, Obara, Naoshi, Kusakabe, Manabu, Yanagimoto, Shintaro, Ogawa, Seishi, Ohshima, Koichi, Chiba, Shigeru·2020·Cancer Research
DOI 10.1158/0008-5472.can-19-2787

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Abstract

Recurrent hotspot (p.Gly17Val) mutations in RHOA encoding a small GTPase, together with loss-of-function mutations in TET2 encoding an epigenetic regulator, are genetic hallmarks of angioimmunoblastic T-cell lymphoma (AITL). Mice expressing the p.Gly17Val RHOA mutant on a Tet2-null background succumbed to AITL-like T-cell lymphomas due to deregulated T-cell receptor (TCR) signaling. Using these mice to investigate therapeutics for AITL, we found that dasatinib, a multikinase inhibitor prolonged their survival through inhibition of hyperactivated TCR signaling. A phase I clinical trial study of dasatinib monotherapy in 5 patients with relapsed/refractory AITL was performed. Dasatinib was started at a dose of 100 mg/body once a day and continued until days 10–78 (median day 58). All the evaluable patients achieved partial responses. Our findings suggest that AITL is highly dependent on TCR signaling and that dasatinib could be a promising candidate drug for AITL treatment. Significance: Deregulated T-cell receptor signaling is a critical molecular event in angioimmunoblastic T-cell lymphoma and can be targeted with dasatinib.

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Metadata

Authors
Nguyen, T. B., Sakata-Yanagimoto, M., Fujisawa, M., Nuhat, S. T., Miyoshi, H., Nannya, Y., Hashimoto, K., Fukumoto, K., Bernard, O. A., Kiyoki, Y., Ishitsuka, K., Momose, H., Sukegawa, S., Shinagawa, A., Suyama, T., Sato, Y., Nishikii, H., Obara, N., Kusakabe, M., Yanagimoto, S., Ogawa, S., Ohshima, K., & Chiba, S.
Affiliations
  • 1Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 3Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 4Department of Pathology, School of Medicine, Kurume University, Kurume, Fukuoka, Japan.
  • 5Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
  • 6Tsukuba Clinical Research and Development Organization, University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 7INSERM U1170, Gustave Roussy, Université Paris-Saclay, Equipe Labellisée Ligue Nationale Contre le Cancer, Villejuif, France.
  • 2Department of Hematology, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.
  • 8Department of Hematology, Hitachi General Hospital, Hitachi, Ibaraki, Japan.
  • 9Department of Hematology, Tsukuba Memorial Hospital, Tsukuba, Ibaraki, Japan.
  • 10Division for Health Service Promotion, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2020-05-01
Volume
80
Issue
9
Pages
1875-1884
ISSN
  • 0008-5472
  • 1538-7445
DOI
10.1158/0008-5472.can-19-2787
Cited by
56
References
2
Language
en
Funders
KAKENHI (18K16077, 18H02834, 16H02660, 19H03684)

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CoChat. (2026). Citation check: Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma. https://app.cochat.ai/papers/10.1158/0008-5472.can-19-2787
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Nguyen, T. B., Sakata-Yanagimoto, M., Fujisawa, M., Nuhat, S. T., Miyoshi, H., Nannya, Y., Hashimoto, K., Fukumoto, K., Bernard, O. A., Kiyoki, Y., Ishitsuka, K., Momose, H., Sukegawa, S., Shinagawa, A., Suyama, T., Sato, Y., Nishikii, H., Obara, N., Kusakabe, M., . . . Chiba, S. (2020). Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma. Cancer Research. https://doi.org/10.1158/0008-5472.can-19-2787