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B cell antigen receptor (BCR) signaling is a key driver of growth and survival in both normal and malignant B cells. Several lines of evidence support an important pathogenic role of the BCR in chronic lymphocytic leukemia (CLL). The significant improvement of CLL patients' survival with the use of various BCR pathway targeting inhibitors, supports a crucial involvement of BCR signaling in the pathogenesis of CLL. Although the treatment landscape of CLL has significantly evolved in recent years, no agent has clearly demonstrated efficacy in patients with treatment-refractory CLL in the long run. To identify new drug targets and mechanisms of drug action in neoplastic B cells, a detailed understanding of the molecular mechanisms of leukemic transformation as well as CLL cell survival is required. In the last decades, studies of genetically modified CLL mouse models in line with CLL patient studies provided a variety of exciting data about BCR and BCR-associated kinases in their role in CLL pathogenesis as well as disease progression. BCR surface expression was identified as a particularly important factor regulating CLL cell survival. Also, BCR-associated kinases were shown to provide a crosstalk of the CLL cells with their tumor microenvironment, which highlights the significance of the cells' milieu in the assessment of disease progression and treatment. In this review, we summarize the major findings of recent CLL mouse as well as patient studies in regard to the BCR signalosome and discuss its relevance in the clinics. [ABSTRACT FROM AUTHOR]

Enhancer of zeste homolog 2 (EZH2) and Bruton's tyrosine kinase (BTK) are both key factors involved in the development and progression of hematological malignancies. Clinical studies have demonstrated the potential of various EZH2 inhibitors, which target the methyltransferase activity of EZH2, for the treatment of lymphomas. However, despite their ability to effectively reduce the H3K27me3 levels, these inhibitors have shown limited efficacy in blocking the proliferation of lymphoma cells. To overcome this challenge, we employed a hydrophobic tagging approach utilizing MS1943, a selective EZH2 degrader. In this study, we investigated the inhibitory effects of two drugs, the FDA-approved EZH2 inhibitor Tazemetostat, currently undergoing clinical trials, and the novel drug MS1943, on Burkitt's lymphoma. Furthermore, we assessed the potential synergistic effect of combining these drugs with the BTK inhibitor Ibrutinib. In this study, we evaluated the effects of combination therapy with MS1943 and Ibrutinib on the proliferation of three Burkitt's lymphoma cell lines, namely RPMI1788, Ramos, and Daudi cells. Our results demonstrated that the combination of MS1943 and Ibrutinib significantly suppressed cell proliferation to a greater extent compared to the combination of Tazemetostat and Ibrutinib. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53- upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt's lymphoma cells. These findings highlight the potential of this innovative therapeutic strategy as an alternative to traditional EZH2 inhibitors, offering promising prospects for improving treatment outcomes in Burkitt's lymphoma. [ABSTRACT FROM AUTHOR]

In the last decade data piled up indicating that BTK - for twenty years considered as a "private matter" of bone marrow-derived cells - it is expressed and plays important and different roles also outside of the hematopoietic compartment and, most notably, in tumor cells. Initial evidence that BTK plays a critical role in B cell-derived malignancies prompted the chase for specific inhibitors, the forefather of which entered the clinic in a record time and paved the way for an ever increasing number of new molecules to be trialed. The growing interests in BTK also led to the discovery that, in solid tumors, two novel isoforms are mainly expressed and actionable liabilities for target therapy. Remarkably, the different isoforms appear to be involved in different signaling pathways which will have to be attentively specified in order to define the area of therapeutic intervention. In this perspective we briefly summarize the progress made in the last decade in studying BTK and its isoforms in cancer cells and define the open questions to be addressed in order to get the most benefits from its targeting for therapeutic purposes. [ABSTRACT FROM AUTHOR]

In the last decade data piled up indicating that BTK – for twenty years considered as a “private matter” of bone marrow-derived cells – it is expressed and plays important and different roles also outside of the hematopoietic compartment and, most notably, in tumor cells. Initial evidence that BTK plays a critical role in B cell-derived malignancies prompted the chase for specific inhibitors, the forefather of which entered the clinic in a record time and paved the way for an ever increasing number of new molecules to be trialed. The growing interests in BTK also led to the discovery that, in solid tumors, two novel isoforms are mainly expressed and actionable liabilities for target therapy. Remarkably, the different isoforms appear to be involved in different signaling pathways which will have to be attentively specified in order to define the area of therapeutic intervention. In this perspective we briefly summarize the progress made in the last decade in studying BTK and its isoforms in cancer cells and define the open questions to be addressed in order to get the most benefits from its targeting for therapeutic purposes.

The BTK inhibitors ibrutinib and acalabrutinib are FDA-approved drugs for the treatment of B cell malignances. Both drugs have demonstrated clinical efficacy and safety profiles superior to chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia. Mounting preclinical and clinical evidence indicates that both ibrutinib and acalabrutinib are versatile and have direct effects on many immune cell subsets as well as other cell types beyond B cells. The versatility and immunomodulatory effects of both drugs have been exploited to expand their therapeutic potential in a wide variety of human diseases. Over 470 clinical trials are currently registered at ClinicalTrials.gov to test the efficacy of ibrutinib or acalabrutinib not only in almost every type of B cell malignancies, but also in hematological malignancies of myeloid cells and T cells, solid tumors, chronic graft versus host disease (cGHVD), autoimmune diseases, allergy and COVID-19 (http:www.clinicaltrials.gov). In this review, we present brief discussions of the clinical trials and relevant key preclinical evidence of ibrutinib and acalabrutinib as monotherapies or as part of combination therapies for the treatment of human diseases beyond B cell malignancies. Adding to the proven efficacy of ibrutinib for cGVHD, preliminary results of clinical trials have shown promising efficacy of ibrutinib or acalabrutinib for certain T cell malignancies, allergies and severe COVID-19. However, both BTK inhibitors have no or limited efficacy for refractory or recurrent solid tumors. These clinical data together with additional pending results from ongoing trials will provide valuable information to guide the design and improvement of future trials, including optimization of combination regimens and dosing sequences as well as better patient stratification and more efficient delivery strategies. Such information will further advance the precise implementation of BTK inhibitors into the clinical toolbox for the treatment of different human diseases. [ABSTRACT FROM AUTHOR]

The BTK inhibitors ibrutinib and acalabrutinib are FDA-approved drugs for the treatment of B cell malignances. Both drugs have demonstrated clinical efficacy and safety profiles superior to chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia. Mounting preclinical and clinical evidence indicates that both ibrutinib and acalabrutinib are versatile and have direct effects on many immune cell subsets as well as other cell types beyond B cells. The versatility and immunomodulatory effects of both drugs have been exploited to expand their therapeutic potential in a wide variety of human diseases. Over 470 clinical trials are currently registered at ClinicalTrials.gov to test the efficacy of ibrutinib or acalabrutinib not only in almost every type of B cell malignancies, but also in hematological malignancies of myeloid cells and T cells, solid tumors, chronic graft versus host disease (cGHVD), autoimmune diseases, allergy and COVID-19 (http:www.clinicaltrials.gov). In this review, we present brief discussions of the clinical trials and relevant key preclinical evidence of ibrutinib and acalabrutinib as monotherapies or as part of combination therapies for the treatment of human diseases beyond B cell malignancies. Adding to the proven efficacy of ibrutinib for cGVHD, preliminary results of clinical trials have shown promising efficacy of ibrutinib or acalabrutinib for certain T cell malignancies, allergies and severe COVID-19. However, both BTK inhibitors have no or limited efficacy for refractory or recurrent solid tumors. These clinical data together with additional pending results from ongoing trials will provide valuable information to guide the design and improvement of future trials, including optimization of combination regimens and dosing sequences as well as better patient stratification and more efficient delivery strategies. Such information will further advance the precise implementation of BTK inhibitors into the clinical toolbox for the treatment of different human diseases.

Tumor microenvironment (TME) plays a crucial role in the initiation and progression of lung adenocarcinoma (LUAD); however, there is still a challenge in understanding the dynamic modulation of the immune and stromal components in TME. In the presented study, we applied CIBERSORT and ESTIMATE computational methods to calculate the proportion of tumor-infiltrating immune cell (TIC) and the amount of immune and stromal components in 551 LUAD cases from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were analyzed by COX regression analysis and protein–protein interaction (PPI) network construction. Then, Bruton tyrosine kinase (BTK) was determined as a predictive factor by the intersection analysis of univariate COX and PPI. Further analysis revealed that BTK expression was negatively correlated with the clinical pathologic characteristics (clinical stage, distant metastasis) and positively correlated with the survival of LUAD patients. Gene Set Enrichment Analysis (GSEA) showed that the genes in the high-expression BTK group were mainly enriched in immune-related activities. In the low-expression BTK group, the genes were enriched in metabolic pathways. CIBERSORT analysis for the proportion of TICs revealed that B-cell memory and CD8+ T cells were positively correlated with BTK expression, suggesting that BTK might be responsible for the preservation of immune-dominant status for TME. Thus, the levels of BTK might be useful for outlining the prognosis of LUAD patients and especially be a clue that the status of TME transition from immune-dominant to metabolic activity, which offered an extra insight for therapeutics of LUAD.

Tumor microenvironment (TME) plays a crucial role in the initiation and progression of lung adenocarcinoma (LUAD); however, there is still a challenge in understanding the dynamic modulation of the immune and stromal components in TME. In the presented study, we applied CIBERSORT and ESTIMATE computational methods to calculate the proportion of tumor-infiltrating immune cell (TIC) and the amount of immune and stromal components in 551 LUAD cases from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were analyzed by COX regression analysis and protein–protein interaction (PPI) network construction. Then, Bruton tyrosine kinase (BTK) was determined as a predictive factor by the intersection analysis of univariate COX and PPI. Further analysis revealed that BTK expression was negatively correlated with the clinical pathologic characteristics (clinical stage, distant metastasis) and positively correlated with the survival of LUAD patients. Gene Set Enrichment Analysis (GSEA) showed that the genes in the high-expression BTK group were mainly enriched in immune-related activities. In the low-expression BTK group, the genes were enriched in metabolic pathways. CIBERSORT analysis for the proportion of TICs revealed that B-cell memory and CD8+ T cells were positively correlated with BTK expression, suggesting that BTK might be responsible for the preservation of immune-dominant status for TME. Thus, the levels of BTK might be useful for outlining the prognosis of LUAD patients and especially be a clue that the status of TME transition from immune-dominant to metabolic activity, which offered an extra insight for therapeutics of LUAD. [ABSTRACT FROM AUTHOR]

Enhancer of zeste homolog 2 (EZH2) and Bruton's tyrosine kinase (BTK) are both key factors involved in the development and progression of hematological malignancies. Clinical studies have demonstrated the potential of various EZH2 inhibitors, which target the methyltransferase activity of EZH2, for the treatment of lymphomas. However, despite their ability to effectively reduce the H3K27me3 levels, these inhibitors have shown limited efficacy in blocking the proliferation of lymphoma cells. To overcome this challenge, we employed a hydrophobic tagging approach utilizing MS1943, a selective EZH2 degrader. In this study, we investigated the inhibitory effects of two drugs, the FDA-approved EZH2 inhibitor Tazemetostat, currently undergoing clinical trials, and the novel drug MS1943, on Burkitt's lymphoma. Furthermore, we assessed the potential synergistic effect of combining these drugs with the BTK inhibitor Ibrutinib. In this study, we evaluated the effects of combination therapy with MS1943 and Ibrutinib on the proliferation of three Burkitt's lymphoma cell lines, namely RPMI1788, Ramos, and Daudi cells. Our results demonstrated that the combination of MS1943 and Ibrutinib significantly suppressed cell proliferation to a greater extent compared to the combination of Tazemetostat and Ibrutinib. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53-upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt's lymphoma cells. These findings highlight the potential of this innovative therapeutic strategy as an alternative to traditional EZH2 inhibitors, offering promising prospects for improving treatment outcomes in Burkitt's lymphoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jeong, Kim, Yang, Yu, Choi, Jeon and Lim.)