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Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma
Tran B Nguyen1, Mamiko Sakata-Yanagimoto2,3, Manabu Fujisawa4
1Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
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.
Insights
Genetic hallmarks of angioimmunoblastic T-cell lymphoma (AITL) involve RHOA and TET2 mutations. Dasatinib, a multikinase inhibitor, shows promise in treating AITL by targeting T-cell receptor signaling.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Angioimmunoblastic T-cell lymphoma (AITL) is characterized by specific genetic mutations.
- Recurrent mutations in RHOA (p.Gly17Val) and TET2 are hallmarks of AITL.
- These mutations lead to deregulated T-cell receptor (TCR) signaling.
Purpose of the Study:
- To investigate potential therapeutics for AITL.
- To evaluate the efficacy of dasatinib in preclinical AITL models and a clinical trial.
- To explore the role of TCR signaling in AITL pathogenesis and treatment.
Main Methods:
- Utilized a mouse model with RHOA (p.Gly17Val) mutation on a Tet2-null background to study AITL.
- Administered dasatinib, a multikinase inhibitor, to mice to assess its impact on survival and TCR signaling.
- Conducted a phase I clinical trial of dasatinib monotherapy in patients with relapsed/refractory AITL.
Main Results:
- Mice with RHOA and Tet2 mutations developed AITL-like lymphomas due to hyperactivated TCR signaling.
- Dasatinib treatment prolonged survival in these mice by inhibiting TCR signaling.
- All evaluable patients in the phase I trial achieved partial responses to dasatinib monotherapy.
Conclusions:
- AITL is critically dependent on deregulated TCR signaling.
- Dasatinib demonstrates potential as an effective therapeutic agent for AITL.
- Targeting TCR signaling pathways offers a promising strategy for AITL treatment.
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