Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma

Tran B Nguyen; Mamiko Sakata-Yanagimoto; Manabu Fujisawa; Sharna Tanzima Nuhat; Hiroaki Miyoshi; Yasuhito Nannya; Koichi Hashimoto; Kota Fukumoto; Olivier A Bernard; Yusuke Kiyoki; Kantaro Ishitsuka; Haruka Momose; Shinichiro Sukegawa; Atsushi Shinagawa; Takuya Suyama; Yuji Sato; Hidekazu Nishikii; Naoshi Obara; Manabu Kusakabe; Shintaro Yanagimoto; Seishi Ogawa; Koichi Ohshima; Shigeru Chiba

doi:10.1158/0008-5472.CAN-19-2787

Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma

Cancer Res. 2020 May 1;80(9):1875-1884. doi: 10.1158/0008-5472.CAN-19-2787. Epub 2020 Feb 27.

Authors

Tran B Nguyen^#¹, Mamiko Sakata-Yanagimoto^#^{2

3}, Manabu Fujisawa⁴, Sharna Tanzima Nuhat⁴, Hiroaki Miyoshi⁵, Yasuhito Nannya⁶, Koichi Hashimoto⁷, Kota Fukumoto⁴, Olivier A Bernard⁸, Yusuke Kiyoki³, Kantaro Ishitsuka³, Haruka Momose³, Shinichiro Sukegawa³, Atsushi Shinagawa⁹, Takuya Suyama⁹, Yuji Sato¹⁰, Hidekazu Nishikii^{1

3}, Naoshi Obara^{1

3}, Manabu Kusakabe^{1

3}, Shintaro Yanagimoto¹¹, Seishi Ogawa⁶, Koichi Ohshima⁵, Shigeru Chiba^{2

3

12}

Affiliations

¹ Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
² Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. [email protected] [email protected].
³ Department of Hematology, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.
⁴ Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
⁵ Department of Pathology, School of Medicine, Kurume University, Kurume, Fukuoka, Japan.
⁶ Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
⁷ Tsukuba Clinical Research and Development Organization, University of Tsukuba, Tsukuba, Ibaraki, Japan.
⁸ INSERM U1170, Gustave Roussy, Université Paris-Saclay, Equipe Labellisée Ligue Nationale Contre le Cancer, Villejuif, France.
⁹ Department of Hematology, Hitachi General Hospital, Hitachi, Ibaraki, Japan.
¹⁰ Department of Hematology, Tsukuba Memorial Hospital, Tsukuba, Ibaraki, Japan.
¹¹ Division for Health Service Promotion, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
¹² Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.

^# Contributed equally.

PMID: 32107212
DOI: 10.1158/0008-5472.CAN-19-2787

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.

Publication types

Clinical Trial, Phase I
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / therapeutic use*
DNA-Binding Proteins / genetics*
Dasatinib / administration & dosage
Dasatinib / therapeutic use*
Dioxygenases
Disease Models, Animal
Drug Administration Schedule
Female
Humans
Immunoblastic Lymphadenopathy / blood
Immunoblastic Lymphadenopathy / drug therapy*
Immunoblastic Lymphadenopathy / genetics
Interferon-gamma / blood
Interleukins / blood
Lymphoma, T-Cell / blood
Lymphoma, T-Cell / drug therapy*
Lymphoma, T-Cell / genetics
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Mice, Transgenic
Middle Aged
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins c-vav / genetics
Receptors, Antigen, T-Cell / drug effects*
Receptors, Antigen, T-Cell / metabolism
Tumor Necrosis Factor-alpha / blood
rhoA GTP-Binding Protein / genetics*

Substances

Antineoplastic Agents
DNA-Binding Proteins
Interleukins
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-vav
Receptors, Antigen, T-Cell
Tumor Necrosis Factor-alpha
VAV1 protein, human
Interferon-gamma
Dioxygenases
TET2 protein, human
Tet2 protein, mouse
rhoA GTP-Binding Protein
Dasatinib