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
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
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...
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
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...
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
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...
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.
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
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
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
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
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
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
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
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
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
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...
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
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...
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
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...
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...
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
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