Reference Detail

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
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 2023).
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, Dec 2022).
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 2022).

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