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 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
Abstract
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.