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Next-generation Bruton's tyrosine kinase (BTK) inhibitors potentially targeting BTK C481S mutation- Recent developments and Perspectives - PubMed

Bruton's tyrosine kinase (BTK) plays a vital role in B-cell antigen receptor (BCR) signalling transduction pathway. Controlling BCR signalling by BTK inhibitors is a promising therapeutic approach for the treatment ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/35927919/


Relevance: In this review, we summarized the discovery and development of next-generation BTK inhibitors, specially targeting to BTK C481S mutation and their applications for the treatment of lymphomas and autoimmune diseases.

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Enrichment of BTK Leu528Trp mutations in Patients with CLL on Zanubrutinib: Potential for Pirtobrutinib Cross Resistance

Research Article | Piers Blombery, Ella R Thompson, Thomas E Lew, Ing Soo Tiong, Rory Bennett, Chan Y Cheah, Katharine Louise Lewis, Sasanka M Handunnetti, Chloe Pek Sang Tang, Andrew ..... see more

Source : https://ashpublications.org/bloodadvances/article/doi/10.1182/bloodadvances.2022008325/486056/Enrichment-of-BTK-Leu528Trp-mutations-in-Patients


Relevance: We describe 2 patients with BTK Leu528Trp mutations who showed clinical cross-resistance and progressive enrichment of the BTK Leu528Trp mutation over time when treated with the non-covalent BTK inhibitor pirtobrutinib. Both patients subsequently responded to venetoclax based treatment. In summary we have identified an enrichment of...

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The potential of pirtobrutinib in multiple B-cell malignancies - PubMed

Bruton's tyrosine kinase (BTK) is a critical downstream signaling element from the B-cell receptor (BCR) that has been effectively inhibited in B-cell cancers by irreversible, covalent inhibitors including ibrutinib and ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/35747462/


Relevance: Here, we review the pharmacologic rationale for pursuing non-covalent BTK inhibitors, the clinical need for such inhibitors, existing safety, and resistance mechanism data for pirtobrutinib, and the forthcoming clinical trials that seek to define the clinical utility of pirtobrutinib, which has the potential to fulfill multiple...

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Integrin Signaling Shaping BTK-Inhibitor Resistance - PubMed

Integrins are adhesion molecules that function as anchors in retaining tumor cells in supportive tissues and facilitating metastasis. Beta1 integrins are known to contribute to cell adhesion-mediated drug resistance in ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/35883678/


Conclusion/Relevance: Bruton's tyrosine kinase (BTK) is a component of B cell receptor signaling and BTK inhibitors such as ibrutinib are highly successful; however, their limitations include indefinite drug administration, the development of therapy resistance, and toxicities. VLA-4 might be activated independently of BTK, resulting in an...

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Risk of bleeding associated with BTK inhibitor monotherapy: a systematic review and meta-analysis of randomized controlled trials

Abstract The risk of bleeding associated with Bruton's tyrosine kinase inhibitor (BTKi) monotherapy remains to be understood. This systematic review aims to evaluate BTKi monotherapy related bleeding risk. PubMed, Embase, ..... see more

Source : https://www.tandfonline.com/doi/abs/10.1080/17512433.2022.2106968?journalCode=ierj20


Conclusions: Ibrutinib and acalabrutinib (vs. control drugs or placebo) have a higher risk of bleeding and overall bleeding, respectively. Limited evidence suggests that ibrutinib (vs. acalabrutinib) significantly increases overall bleeding risk, but the differences are not observed in other comparisons.

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Dual Targeting of Anti-Apoptotic Proteins Enhances Chemosensitivity of the Acute Myeloid Leukemia Cells

Document Type : Research Articles Authors 1 Immunology Research Center, Tabriz University of Medical sciences, Tabriz, Iran. 2 Department of Immunology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, ..... see more

Source : https://journal.waocp.org/article_90207.html


Conclusions: Our investigation suggests that suppression of Mcl-1 and survivin by siRNA can effectually inhibit cell growth and overcome chemoresistance of AML cells. Therefore siRNAs may be an important adjuvant in chemotherapy for AML patients.

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Integrin Signaling Shaping BTK-Inhibitor Resistance - PubMed

Integrins are adhesion molecules that function as anchors in retaining tumor cells in supportive tissues and facilitating metastasis. Beta1 integrins are known to contribute to cell adhesion-mediated drug resistance in ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/35883678/


Relevance: In this context, we discuss the inside-out signaling cascade culminating in VLA-4 activation, consider the advantages and disadvantages of BTK inhibitors in CLL and elucidate the mechanisms behind cell adhesion-mediated drug resistance.

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Enrichment of BTK Leu528Trp mutations in Patients with CLL on Zanubrutinib: Potential for Pirtobrutinib Cross Resistance

Research Article | Piers Blombery, Ella R Thompson, Thomas E Lew, Ing Soo Tiong, Rory Bennett, Chan Y Cheah, Katharine Louise Lewis, Sasanka M Handunnetti, Chloe Pek Sang Tang, Andrew ..... see more

Source : https://ashpublications.org/bloodadvances/article/doi/10.1182/bloodadvances.2022008325/486056/Enrichment-of-BTK-Leu528Trp-mutations-in-Patients


Conclusion: In summary we have identified an enrichment of the BTK Leu528Trp mutation arising in patients treated with zanubrutinib which may impart cross-resistance to the non-covalent inhibitor pirtobrutinib and therefore implications for sequencing of these treatments in CLL.

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Bruton's Tyrosine Kinase phosphorylates scaffolding and RNA-binding protein G3BP1 to induce stress granule aggregation during host sensing of foreign ribonucleic acids

The Ras-GTPase activating protein SH3 domain-binding protein 1 (G3BP1) plays a critical role in the formation of classical and anti-viral stress granules in stressed and virus-infected eukaryotic cells, respectively. While ..... see more

Source : https://www.jbc.org/article/S0021-9258(22)00673-1/fulltext


Conclusion: Taken together, our data indicate that BTK phosphorylation of G3BP1 induces G3BP1 oligomerization and facilitates the condensation of ribonucleoprotein complexes into macromolecular aggregates.

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Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib

Recent clinical trials show promising results for the next-generation Bruton's tyrosine kinase (BTK) inhibitor evobrutinib in the treatment of multiple sclerosis (MS). BTK has a central role in signaling pathways ..... see more

Source : https://insight.jci.org/articles/view/160909


Conclusion/Relevance: These findings demonstrate a functional link between BTK activity and disease-relevant B cells and offer valuable insights into how next-generation BTK inhibitors could modulate the clinical course in MS patients.

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Comparison of inhibitory effects of irreversible and reversible Btk inhibitors on platelet function - PubMed

All irreversible Bruton tyrosine kinase (Btk) inhibitors including ibrutinib and acalabrutinib induce platelet dysfunction and increased bleeding risk. New reversible Btk inhibitors were developed, like MK-1026. The mechanism underlying increased ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/35845214/


Conclusion: As MK-1026 showed less off-target effects and only affected activation of isolated platelets, it might be promising for future treatment.

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Practical management of chronic lymphocytic leukemia with acalabrutinib

Abstract Abstract Treatment of chronic lymphocytic leukemia (CLL) has been transformed in the past two decades. The introduction of targeted therapies has improved patient outcomes and the deliverability of effective ..... see more

Source : https://www.tandfonline.com/doi/full/10.1080/10428194.2022.2098289


Conclusion: Acalabrutinib represents a well-tolerated and effective alternative to ibrutinib in the management of CLL.

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Role of high acquisition flow cytometry in the detection of marrow involvement in patients with extramedullary B cell non-Hodgkins lymphoma: a comparison with marrow aspirate cytology, trephine biopsy, and PET

Abstract Detection of marrow infiltration is crucial in extramedullary B cell non-Hodgkin lymphoma (B-NHL). We studied the efficiency of high acquisition flow cytometry (FCM) in detecting marrow involvement in B-NHL ..... see more

Source : https://www.tandfonline.com/doi/abs/10.1080/10428194.2022.2092858?journalCode=ilal20


Conclusion: This study shows that a combination of PET and FCM with high event acquisition is the best way for assessing marrow involvement in B-NHL cases.

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Estrogen Receptor β (ESR2) Transcriptome and Chromatin Binding in a Mantle Cell Lymphoma Tumor Model Reveal the Tumor-Suppressing Mechanisms of Estrogens - PubMed

Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma with one of the highest male-to-female incidence ratios. The reason for this is not clear, but epidemiological as well as experimental data ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/35804870/


Conclusion: The results clarify the mechanisms by which estrogens, via ESR2, impair MCL tumor progression and provide a possible explanation for the sex-dependent difference in incidence. Furthermore, targeting ESR2 with a selective agonist may be an additional option when considering the treatment of both ibrutinib-sensitive and -resistant...

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In Vitro and In Vivo Models of CLL-T Cell Interactions: Implications for Drug Testing - PubMed

T cells are key components in environments that support chronic lymphocytic leukemia (CLL), activating CLL-cell proliferation and survival. Here, we review in vitro and in vivo model systems that mimic ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/35804862/


Relevance: We discuss approaches for direct CLL-cell co-culture with autologous T cells, models utilizing supportive cell lines engineered to express T-cell factors (such as CD40L) or stimulating CLL cells with combinations of recombinant factors (CD40L, interleukins IL4 or IL21, INFγ) and additional B-cell receptor (BCR) activation with...

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Tumor Microenvironment and Immunotherapy-Based Approaches in Mantle Cell Lymphoma - PubMed

1 Department of Hematology, Gustave Roussy Cancer Campus, 94805 Villejuif, France. 2 Department of Hematology, Necker Hospital, Assistance Publique des Hopitaux de Paris (APHP), 75004 Paris, France. 3 Nantes Universite, ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/35804999/


Relevance: Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t(11;14) (q13;q32) and a poor response to rituximab-anthracycline-based chemotherapy. High-dose cytarabine-based regimens offer a durable response, but an important number of MCL patients are not eligible for intensive...

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Mechanisms of resistance to noncovalent Bruton's tyrosine kinase inhibitors | Mission Bio

Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations ..... see more

Source : https://missionbio.com/resources/publications/wang-nejm-2022/


Conclusions: Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established...

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A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia - PubMed

B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/35743155/

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Zanubrutinib in Treating Waldenström Macroglobulinemia | TCRM

B-cell development, survival, and expansion is critically dependent on normally functioning and tightly regulated B-cell receptor (BCR) signaling pathways. Key mediators of the BCR pathway include the proximal kinases - ..... see more

Source : https://www.dovepress.com/zanubrutinib-in-treating-waldenstrm-macroglobulinemia-the-last-shall-b-peer-reviewed-fulltext-article-TCRM


Conclusion: Even though zanubrutinib has been the third and last BTK inhibitor to currently penetrate the market for B-cell lymphoproliferative malignancies, we highlight the emergence of zanubrutinib as a key player in the forefront of the therapeutic landscape in WM.