High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell–like diffuse large B-cell lymphoma cells

Griner, Lesley A. Mathews; Guha, Rajarshi; Shinn, Paul; Young, Ryan M.; Keller, Jonathan M.; Liu, Dongbo; Goldlust, Ian S.; Yasgar, Adam; McKnight, Crystal; Boxer, Matthew B.; Duveau, Damien Y.; Jiang, Jian‐kang; Michael, Sam; Mierzwa, Tim; Huang, Wenwei; Walsh, Martin J.; Mott, Bryan T.; Patel, Paresma; Leister, William; Maloney, David J.; LeClair, Christopher A.; Rai, Ganesha; Jadhav, Ajit; Peyser, Brian D.; Austin, Christopher P.; Martin, Scott E.; Simeonov, Anton; Ferrer, Marc; Staudt, Louis M.; Thomas, Craig J.

doi:10.1073/pnas.1311846111

Cited by 352 publications

(286 citation statements)

References 52 publications

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“…Although secondgeneration Btk inhibitors with promising efficacy profiles have been developed (37,38), it is expected that combination regimens will result in long-lasting responses, as they may overcome resistance. Indeed, combining ibrutinib with a PI3K or Akt pathway inhibitor was shown to have synergistic effects (36,(39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling

Bruijn

Rip

Ploeg

et al. 2017

The Journal of Immunology

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The Tec tyrosine kinase is expressed in many cell types, including hematopoietic cells, and is a member of the Tec kinase family that also includes Btk. Although the role of Btk in B cells has been extensively studied, the role of Tec kinase in B cells remains largely unclear. It was previously shown that Tec kinase has the ability to partly compensate for loss of Btk activity in B cell differentiation, although the underlying mechanism is unknown. In this study, we confirm that Tec kinase is not essential for normal B cell development when Btk is present, but we also found that Tec-deficient mature B cells showed increased activation, proliferation, and survival upon BCR stimulation, even in the presence of Btk. Whereas Tec deficiency did not affect phosphorylation of phospholipase Cγ or Ca2+ influx, it was associated with significantly increased activation of the intracellular Akt/S6 kinase signaling pathway upon BCR and CD40 stimulation. The increased S6 kinase phosphorylation in Tec-deficient B cells was dependent on Btk kinase activity, as ibrutinib treatment restored pS6 to wild-type levels, although Btk protein and phosphorylation levels were comparable to controls. In Tec-deficient mice in vivo, B cell responses to model Ags and humoral immunity upon influenza infection were enhanced. Moreover, aged mice lacking Tec kinase developed a mild autoimmune phenotype. Taken together, these data indicate that in mature B cells, Tec and Btk may compete for activation of the Akt signaling pathway, whereby the activating capacity of Btk is limited by the presence of Tec kinase.

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Section: Discussionmentioning

confidence: 99%

Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling

Bruijn

Rip

Ploeg

et al. 2017

The Journal of Immunology

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“…Moreover, we have shown that the combination of Ibrutinib with the dual PI3K/mTOR inhibitor BEZ235 synergistically inhibits cell viability of ErbB2+ breast cancer cells. Recently, a synergistic interaction between Ibrutinib and a wide range of compounds targeting the PI3K/AKT/mTOR-signaling cascade, including BEZ235, was demonstrated in an activated B-cell-like subtype of diffuse large B-cell lymphoma [31]. The development of efficient drug combination regimes in the treatment of cancer is a promising therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib (ImbruvicaTM) potently inhibits ErbB receptor phosphorylation and cell viability of ErbB2-positive breast cancer cells

Grabinski

Ewald

2014

Invest New Drugs

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Ibrutinib (formerly PCI-32765) is a specific, irreversible, and potent inhibitor of Burton's tyrosine kinase (BTK) developed for the treatment of several forms of blood cancer. It is now an FDA-approved drug marketed under the name Imbruvica(TM) (Pharmacyclics, Inc.) and successfully used as an orally administered second-line drug in the treatment of mantle cell lymphoma. Since BTK is predominantly expressed in hematopoietic cells, the sensitivity of solid tumor cells to Ibrutinib has not been analyzed. In this study, we determined the effect of Ibrutinib on breast cancer cells. We demonstrate that Ibrutinib efficiently reduces the phosphorylation of the receptor tyrosine kinases ErbB1, ErbB2 and ErbB3, thereby suppressing AKT and MAPK signaling in ErbB2-positive (ErbB2+) breast cancer cell lines. Treatment with Ibrutinib significantly reduced the viability of ErbB2+ cell lines with IC50 values at nanomolar concentrations, suggesting therapeutic potential of Ibrutinib in breast cancer. Combined treatment with Ibrutinib and the dual PI3K/mTOR inhibitor BEZ235 synergistically reduces cell viability of ErbB2+ breast cancer cells. Combination indices below 0.25 at 50% inhibition of cell viability were determined by the Chou-Talalay method. Therefore, the combination of Ibrutinib and canonical PI3K pathway inhibitors could be a new and effective approach in the treatment of breast cancer with activated ErbB receptors. Ibrutinib could thus become a valuable component of targeted therapy in aggressive ErbB2+ breast cancer.

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“…In normal B-cells treated by ibrutinib, a decrease in the expression of other antiapoptotic proteins like BCL2A1 and Bcl-XL has been reported [20]. The effect of DXM/ibrutinib combination on lymphocyte cell death has already been observed in vitro in diffuse large B-cell lymphoma cell line in which ibrutinib input potentiated cell viability reduction [27]. Once again DXM addition to ibrutinib treatment could reinforce its activity and notably apoptotis induction via Syk inhibition and also Mcl-1 downregulation.…”

Section: Discussionmentioning

confidence: 97%

The ibrutinib B-cell proliferation inhibition is potentiated in vitro by dexamethasone: Application to chronic lymphocytic leukemia

et al. 2016

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High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell–like diffuse large B-cell lymphoma cells

Cited by 352 publications

References 52 publications

Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling

Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling

Ibrutinib (ImbruvicaTM) potently inhibits ErbB receptor phosphorylation and cell viability of ErbB2-positive breast cancer cells

The ibrutinib B-cell proliferation inhibition is potentiated in vitro by dexamethasone: Application to chronic lymphocytic leukemia

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