Phase I/<scp>II</scp> study of dasatinib and exploratory genomic analysis in relapsed or refractory non‐Hodgkin lymphoma

Umakanthan, Jayadev Manikkam; Iqbal, Javeed; Batlevi, Connie Lee; Bouska, Alyssa; Smith, Lynette M.; Shostrom, Valerie; Nutsch, Heather; William, Basem M.; Bociek, R. Gregory; Lunning, Matt; Bierman, Philip J.; Younes, Anas; Armitage, Jamés O.; Vose, Julie M.

doi:10.1111/bjh.15702

Cited by 23 publications

(20 citation statements)

References 44 publications

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“…This patient's response suggests that G17V RHOA or VAV1 mutations do not necessarily predict dasatinib efficacy in AITL. Meanwhile, a phase I/II study of dasatinib as treatment for relapse/refractory non-Hodgkin lymphomas reported a patient with AITL achieving a PR, in agreement with our study (33).…”

Section: Discussionsupporting

confidence: 91%

Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma

et al. 2020

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◥ 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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Section: Discussionsupporting

confidence: 91%

Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma

et al. 2020

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“…Dasatinib has been previously examined for its potential activity against non-Hodgkin lymphoma in a phase 1/2 clinical trial including 33 patients with heterogeneous B-and T-NHL histologies (30). Although it showed a limited number of both partial and complete responses with acceptable toxicities, this study included only 8 DLBCLs and did not explore the status of PI3K/AKT/ mTOR activation in these cases.…”

Section: Discussionmentioning

confidence: 99%

Repurposing dasatinib for diffuse large B cell lymphoma

Scuoppo

Wang

Persaud

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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To repurpose compounds for diffuse large B cell lymphoma (DLBCL), we screened a library of drugs and other targeted compounds approved by the US Food and Drug Administration on 9 cell lines and validated the results on a panel of 32 genetically characterized DLBCL cell lines. Dasatinib, a multikinase inhibitor, was effective against 50% of DLBCL cell lines, as well as against in vivo xenografts. Dasatinib was more broadly active than the Bruton kinase inhibitor ibrutinib and overcame ibrutinib resistance. Tumors exhibiting dasatinib resistance were commonly characterized by activation of the PI3K pathway and loss of PTEN expression as a specific biomarker. PI3K suppression by mTORC2 inhibition synergized with dasatinib and abolished resistance in vitro and in vivo. These results provide a proof of concept for the repurposing approach in DLBCL, and point to dasatinib as an attractive strategy for further clinical development in lymphomas.

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“…We provide evidence that targeting LCK kinase activity with dasatinib has potent inhibitory effects on KHDRBS1-LCK-driven signaling, paving the way for therapeutic intervention in a clinical setting. Early-stage clinical trials suggest activity of dasatinib in PTCL-NOS 48 and TFH-related PTCL 49 . With the identi cation of the KHDRBS1-LCK gene fusion, we provide an additional biological basis to repurpose dasatinib for the treatment of PTCL-NOS.…”

Section: Discussionmentioning

confidence: 99%

FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T cell lymphoma, not otherwise specified

Debackere¹,

Marcelis²,

Demeyer³

et al. 2021

Preprint

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Peripheral T cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we performed RNA-sequencing of 18 cases and validated results in an independent cohort of 37 PTCL cases. We identified FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs.

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Phase I/II study of dasatinib and exploratory genomic analysis in relapsed or refractory non‐Hodgkin lymphoma

Cited by 23 publications

References 44 publications

Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma

Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma

Repurposing dasatinib for diffuse large B cell lymphoma

FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T cell lymphoma, not otherwise specified

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