Dasatinib therapy results in decreased B cell proliferation, splenomegaly, and tumor growth in a murine model of lymphoma expressing Myc and Epstein-Barr virus LMP2A

Dargart, Jamie L.; Fish, Kamonwan; Li, Gordon; Longnecker, Richard; Çen, Osman

doi:10.1016/j.antiviral.2012.05.003

Cited by 27 publications

(31 citation statements)

References 49 publications

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“…2A). These results parallel values reported in the literature for inhibition of BTK, PI3K␦, and LYN enzymatic activities (8)(9)(10). As shown in Fig.…”

Section: Resultssupporting

confidence: 81%

“…Thus, the pharmacodynamics of inhibition of EBV lytic induction paralleled the inhibition of the expected target pathway, i.e., ibrutinib, idelalisib, and dasatinib all inhibited phosphorylation of AKT, extracellular signal-regulated kinase (ERK), and PI3K. Note that clinically dasatinib is used to inhibit ABL kinase and inhibition of LYN is an off-target effect (10). To validate the specificity of the drugs on their target genes, we performed small interfering RNA (siRNA) knockdown experiments against BTK, LYN, and PI3K (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation

Kosowicz

Lee

Peiffer

et al. 2017

J Virol

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Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block B cell receptor (BCR) signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction. Further investigation shows that mammalian target of rapamycin complex 2 (mTORC2) contributes to BCR-mediated lytic induction and that FK506-binding protein 12 (FKBP12) binding alone is not adequate to block activation. Finally, we show that BCR signaling can activate EBV lytic induction in freshly isolated B cells from peripheral blood mononuclear cells (PBMCs) and that activation can be inhibited by ibrutinib or idelalisib.IMPORTANCE EBV establishes viral latency in B cells. Activation of the B cell receptor pathway activates lytic viral expression in cell lines. Here we show that drugs that inhibit important kinases in the BCR signaling pathway inhibit activation of lytic viral expression but do not inhibit several other lytic activation pathways. Immunosuppressant drugs such as cyclosporine and tacrolimus but not rapamycin also inhibit BCR-mediated EBV activation. Finally, we show that BCR activation of lytic infection occurs not only in tumor cell lines but also in freshly isolated B cells from patients and that this activation can be blocked by BCR inhibitors.KEYWORDS B cell receptor pathway, cyclosporine, dasatinib, Epstein-Barr virus, ibrutinib, idelalisib, lytic infection, rapamycin, tacrolimus, mTOR E pstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus infection that is maintained in a pool of resting memory B cells following primary infection (1-3).The disappearance of B cells from blood as assessed by flow cytometry following treatment with a B cell-targeting monoclonal antibody commonly results in an inability to detect EBV DNA in peripheral blood mononuclear cells (PBMCs) (4). The reservoir in B cells appears to be necessary to maintain the virus as evidenced by the observation that chronic infection is not established in patients with Bruton agammaglobulinemia who lack B cells (3). B cells not only harbor the virus, but the character of the B cells that harbor virus influence viral gene regulation. In vitro, EBV infection of B cells results in immortalized lymphoblastoid cell lines expressing eight or more latency antigens, whereas in vivo, in healthy seropositive adults, the B cells that harbor viral genomes demonstrate very restricted viral gene expression. The germinal center reaction that occurs in lymphoid tissue is hypothesized to play a key role in downmodulating viral gene expression (1). In some B cell tumor lines, B cell receptor (BCR) signaling is a potent activator of EBV lytic gene expression (5). EBV gene expression and particularly

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“…2A). These results parallel values reported in the literature for inhibition of BTK, PI3K␦, and LYN enzymatic activities (8)(9)(10). As shown in Fig.…”

Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation

Kosowicz

Lee

Peiffer

et al. 2017

J Virol

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show abstract

“…37 Inhibition of Akt induces apoptosis in B cells from LMP2A transgenic mice. 59 Furthermore, the inhibition of the Lyn kinase or the mammalian target of rapamycin (mTOR) pathway leads to decreases in spleen and tumor sizes in LMP2A/l-MYC mice compared with l-MYC mice, 60,61 suggesting that LMP2A is able to mimic the BCR signal through the Akt/mTOR pathway to promote lymphomagenesis.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr virus latent membrane protein 2A enhances MYC-driven cell cycle progression in a mouse model of B lymphoma

Fish

Chen

Longnecker

2014

Blood

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“…Beside Btk, the direct inhibitory activity of IQS019 towards Syk and/or Lyn phosphorylation may also explain the capacity of the compound to activate apoptosis in vitro and in vivo, as pharmacological inhibition of Syk, has been reported to elicit the apoptotic cascade in preclinical models of DLBCL and CLL [35, 36]. Also, probably thanks to its apoptogenic property and specificity, IQS019 salt is found to be significantly active and safe at a dose of 2 mg/kg/day, which is much lower than the reported active concentrations of fostamatinib, dasatinib or ibrutinib in mouse models of lymphoid neoplasms [37–39], thus predicting a probable low incidence of secondary adverse effects of the compound.…”

Section: Discussionmentioning

confidence: 99%

Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma

et al. 2017

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BackgroundPharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton’s kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents.MethodsWe evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib. Safety and efficacy of the compound were then evaluated in two xenograft mouse models of B cell lymphoma.ResultsIQS019 simultaneously engaged a rapid and dose-dependent de-phosphorylation of both constitutive and IgM-activated Syk, Lyn, and Btk, leading to impaired cell proliferation, reduced CXCL12-dependent cell migration, and induction of caspase-dependent apoptosis. Accordingly, B cell lymphoma-bearing mice receiving IQS019 presented a reduced tumor outgrowth characterized by a decreased mitotic index and a lower infiltration of malignant cells in the spleen, in tight correlation with downregulation of phospho-Syk, phospho-Lyn, and phospho-Btk. More interestingly, IQS019 showed improved efficacy in vitro and in vivo when compared to the first-in-class Btk inhibitor ibrutinib, and was active in cells with acquired resistance to this latest.ConclusionsThese results define IQS019 as a potential drug candidate for a variety of B lymphoid neoplasms, including cases with acquired resistance to current BCR-targeting therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0447-6) contains supplementary material, which is available to authorized users.

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Dasatinib therapy results in decreased B cell proliferation, splenomegaly, and tumor growth in a murine model of lymphoma expressing Myc and Epstein-Barr virus LMP2A

Cited by 27 publications

References 49 publications

Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation

Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation

Epstein-Barr virus latent membrane protein 2A enhances MYC-driven cell cycle progression in a mouse model of B lymphoma

Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma

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