Identification of Bruton’s tyrosine kinase as a therapeutic target in acute myeloid leukemia

Rushworth, Stuart A.; Murray, Megan Y.; Zaitseva, Lyubov; Bowles, Kristian M.; MacEwan, David J.

doi:10.1182/blood-2013-06-511154

Cited by 104 publications

(121 citation statements)

References 55 publications

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“…We generated artificial and exogenous miRNA sequences specifically targeting the BTK transcript [miRBTK] and utilised lenti-viral infection to achieve semi-stable BTK mRNA knockdown [as described previously 25 ] in both bortezomib-na€ ıve and bortezomib-resistant U266 MM cells (Fig. 4A).…”

Section: Pharmacological Btk Inhibition With Ibrutinib Restores Sensimentioning

confidence: 99%

“…p65 staining intensity was performed using ImageJ 1.46 software (National Institute of Health) and plugins, as described previously. 25 Briefly, a threshold of staining intensity was applied and the area above the threshold (pixles 2 ) was measured (n 80 [BTK] and n 20 [NF-kB] individual cells). Staining intensity (pixles 2 ) was converted to a percentage as follows: pBTK/total BTK (%), or, nuclear/[cytoplasmic C nuclear NF-kB p65] (%).…”

Section: Quantification Of Protein Activity and Subcellular Localizatmentioning

confidence: 99%

“…0 ]) or a control/scrambled sequence (miR-NEG), and an EmGFP-pre-miRNA encoding fragment, were constructed and produced as described previously. 25 Briefly, artificial miRNA targets were identified and designed to interact with the relevant exon using Block-iT RNAi designer software (Invitrogen). This ensures high specificity of miR-p65 and miR-BTK, with no 3 0 UTR interaction, unlike endogenous miRNAs.…”

Section: Rna Extraction and Quantitative Real Time-pcrmentioning

confidence: 99%

“…22 BTK, a non-receptor tyrosine kinase, is now known to be of key importance to a number of haematological malignancies, including MM, 23 chronic lymphocytic leukemia (CLL) 24 and acute myeloid leukemia (AML). 25 The potential feedback mechanism between NF-kB and BTK signaling, whereby BTK also lies upstream of several NF-kB inducible signaling pathways, 26,27 provides a rationale for investigation of combined NF-kB and BTK inhibition in MM.…”

Section: Introductionmentioning

confidence: 99%

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Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

et al. 2015

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Abbreviations: MM -multiple myeloma; PI -proteasome inhibitor; NF-kB -nuclear factor-kappa B; BMSC -bone marrow stromal cells; BTK -Bruton's tyrosine kinase.Multiple Myeloma (MM) is a haematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow. Over the last 10-15 y the introduction of the proteasome-inhibitor bortezomib has improved MM prognosis, however relapse due to bortezomib-resistance is inevitable and the disease, at present, remains incurable. To model bortezomib-resistant MM we generated bortezomib-resistant MM cell lines (n D 4 ) and utilised primary malignant plasma cells from patients relapsing after bortezomib treatment (n D 6 ). We identified enhanced Bruton's tyrosine kinase (BTK) activity in bortezomib-resistant MM cells and found that inhibition of BTK, either pharmacologically with ibrutinib (0.5 mM) or via lenti-viral miRNA-targeted BTK interference, re-sensitized previously bortezomib-resistant MM cells to further bortezomib therapy at a physiologically relevant concentration (5 nM). Further analysis of pro-survival signaling revealed a role for the NF-kB p65 subunit in MM bortezomib-resistance, thus a combination of BTK and NF-kB p65 inhibition, either pharmacologically or via further lenti-viral miRNA NF-kB p65 interference, also restored sensitivity to bortezomib, significantly reducing cell viability (37.5 § 6 .9 %, ANOVA P 0 .001). Accordingly, we propose the clinical evaluation of a bortezomib/ibrutinib combination therapy, including in patients resistant to single-agent bortezomib.

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Section: Pharmacological Btk Inhibition With Ibrutinib Restores Sensimentioning

confidence: 99%

Section: Quantification Of Protein Activity and Subcellular Localizatmentioning

confidence: 99%

Section: Rna Extraction and Quantitative Real Time-pcrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

et al. 2015

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“…This level of ibrutinib sensitivity was comparable to that of primary human CLL tumor cells. 19,20 By contrast, A20 tumor cells were insensitive to ibrutinib (IC50 .10 mM; Figure 1C). Similar IC50 values were obtained when fresh ibrutinib was introduced daily.…”

Section: Sensitivity Of B-lineage Tumor Cells To Ibrutinib and To Cpgmentioning

confidence: 99%

Ibrutinib enhances the antitumor immune response induced by intratumoral injection of a TLR9 ligand in mouse lymphoma

Sagiv-Barfi

Kohrt

Burckhardt

et al. 2015

Blood

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• The combination of intratumoral CpG with systemic ibrutinib results in complete and permanent regression of both local and distant tumors.• The antitumor effect of the combination is T-cell dependent.We have designed a novel therapeutic approach for lymphoma that combines targeted kinase inhibition with in situ vaccination. Intratumoral injection of an unmethylated cytosine guanine dinucleotide (CpG)-enriched oligodeoxynucleotide, an agonist for the toll-like receptor 9 (TLR9), induces the activation of natural killer cells, macrophages, and antigen presenting cells that control tumor growth at the local site. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, a key enzyme in the signaling pathway downstream of B-cell receptor, is an effective treatment against many types of B-cell lymphomas. The combination of intratumoral injection of CpG with systemic treatment by ibrutinib resulted in eradication of the tumors not only in the injected site, but also at distant sites. Surprisingly, this combinatorial antitumor effect required an intact T-cell immune system since it did not occur in nude, severe combined immunodeficiency, or T-cell depleted mice. Moreover, T cells from animals treated with intratumoral CpG and ibrutinib prevented the outgrowth of newly injected tumors. This result suggests that ibrutinib can induce immunogenic cell death of lymphoma cells and that concomitant stimulation of antigen-presenting cells in the tumor microenvironment by toll-like receptor ligands can lead to a powerful systemic antitumor immune response. (Blood. 2015;125(13):2079-2086

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Abivertinib synergistically strengthens the anti‐leukemia activity of venetoclax in acute myeloid leukemia in a BTK‐dependent manner

Huang

Zhang

et al. 2020

Molecular Oncology

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B-cell lymphoma 2 (BCL-2), a crucial member of the anti-apoptotic BCL-2 family, is frequently dysregulated in cancer and plays an important role in acute myeloid leukemia (AML). Venetoclax is a highly selective BCL-2 inhibitor that has been approved by the FDA for treating elderly AML patients. However, the emergence of resistance after long-term treatment emphasizes the need for a deeper understanding of the potential mechanisms of resistance and effective rescue methods. By using RNA-seq analysis in two human AML cohorts made up of three patients with complete remission and three patients without remission after venetoclax treatment, we identified that upregulation of BTK enabled AML blast resistance to venetoclax. Interestingly, we found that abivertinib, an oral BTK inhibitor, could synergize with venetoclax to inhibit the proliferation of primary AML cells and cell lines. It is worth noting that the combination of the two effectively enhanced the sensitivity of two AML patients (AML#3 and AML#12) to venetoclax. In this study, we demonstrated that combined use of the two drugs can synergistically inhibit the colony-forming capacity of AML cells, arrest the AML cell cycle in the G0/G1 phase, and inhibit the BCL-2 anti-apoptotic family protein, activating the caspase family to induce apoptosis. Mechanistically, knockdown of BTK in AML cell lines impaired the synergistic effect of the two drugs. In vivo study showed similar results as those seen in vitro. Abivertinib in combination with venetoclax could significantly prolong the survival time and reduce the tumor burden of MV4-11-NSG mice compared with those of control and single-agent groups. Our in vitro and in vivo studies have shown that the combination of abivertinib and venetoclax may benefit AML patients, especially in patients resistant to venetoclax or those that relapse. New clinical trials will be planned.

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Identification of Bruton’s tyrosine kinase as a therapeutic target in acute myeloid leukemia

Cited by 104 publications

References 55 publications

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

Ibrutinib enhances the antitumor immune response induced by intratumoral injection of a TLR9 ligand in mouse lymphoma

Abivertinib synergistically strengthens the anti‐leukemia activity of venetoclax in acute myeloid leukemia in a BTK‐dependent manner

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