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Ref Type Journal Article
PMID (32107212)
Authors Nguyen TB, Sakata-Yanagimoto M, Fujisawa M, Nuhat ST, Miyoshi H, Nannya Y, Hashimoto K, Fukumoto K, Bernard OA, 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
Title Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 80 9 2020 05 01 1875-1884 Cancer Res
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ATM D1285G missense unknown ATM D1285G does not lie within any known functional domains of the Atm protein (UniProt.org). D1285G has been identified in sequencing studies (PMID: 32107212), but has not been biochemically characterized and therefore, its effect on Atm protein function is unknown (PubMed, Dec 2024).
TET2 E1207K missense unknown TET2 E1207K lies within the catalytic domain of the Tet2 protein (PMID: 24315485). E1207K has been identified in sequencing studies (PMID: 30279227, PMID: 32107212), but has not been biochemically characterized and therefore, its effect on Tet2 protein function is unknown (PubMed, Nov 2024).
TET2 G1814* nonsense unknown TET2 G1814* results in a premature truncation of the Tet2 protein at amino acid 1814 of 2002 (UniProt.org). G1814* has been identified in sequencing studies (PMID: 32107212), but has not been biochemically characterized and therefore, its effect on Tet2 protein function is unknown (PubMed, Nov 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TET2 T1063Nfs*5 TET2 E1207K angioimmunoblastic T-cell lymphoma predicted - sensitive Dasatinib Case Reports/Case Series Actionable In a Phase I trial, four patients with relapsed/refractory angioimmunoblastic T-cell lymphoma harboring TET2 mutations and/or RHOA G17V achieved a partial response within 30 days of Sprycel (dasatinib) treatment, including one patient harboring TET2 T1063Nfs*5 and TET2 E1207K who maintained the partial response at the time of trial discontinuation (PMID: 32107212). 32107212