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Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors to venetoclax

ABSTRACT: Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors to venetoclax

PROVIDER: PRJNA1111487 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29021583_1.fastq.gz	Fastqsanger.gz
	SRR29021583_2.fastq.gz	Fastqsanger.gz
	SRR29021584_1.fastq.gz	Fastqsanger.gz
	SRR29021584_2.fastq.gz	Fastqsanger.gz
	SRR29021585_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors to venetoclax

Project description:Disparate mechanisms of pathogenesis have thwarted implementation of precision medicine approaches for the treatment of diffuse large B-cell lymphoma (DLBCL), the most frequently diagnosed hematologic malignancy in the United States. Though curable with combination chemoimmunotherapy in many newly diagnosed patients, DLBCL carries persistently poor prognosis for those with relapsed or refractory (rel/ref) disease, despite recent advances in immunotherapy. Here, we build on recent findings implicating gain-of-function mutations in the BCL10 signaling protein as drivers of resistance to Bruton’s tyrosine kinase (BTK) inhibitors. We show mutant BCL10-driven DLBCL models are resistant to multiple additional drug classes, demonstrating urgency to derive mechanistically rooted treatment strategies to overcome undruggable BCL10 mutants that form stable BTK-independent signaling filaments upstream of NF-kB activation. BCL10 mutants promote a cytokine-reinforced positive feedback loop of lymphomagenesis driving not just NF-kB but multiple additional pathways converging on diffuse activation of oncogenic transcription factors. Up-regulation of multiple anti-apoptotic genes promotes increased mitochondrial membrane potential, a key factor underlying multidrug resistance. Increased expression of BCL2, BCL2L1 (BCL-XL), and BCL2A1 (BFL1) drives resistance to the BCL2 inhibitor venetoclax, but further investigation revealed expression is overcome by the potent non-covalent BTK inhibitor pirtobrutinib. Venetoclax plus pirtobrutinib synergized in overcoming resistance and potently killed BCL10- mutant DLBCL tumors in vitro and in vivo. BTK therefore retains key roles protecting DLBCL tumors from apoptosis even when direct downstream activation of the BCL10 signaling complex activates NF-kB independently.

2025-02-12 | GSE267421 | GEO

Targeting mitochondrial structure sensitizes AML to Venetoclax

Project description:The BCL-2 family plays important roles in acute myeloid leukemia (AML) and Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML cells to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.

2019-05-03 | GSE125403 | GEO

Inhibitors of Bcl-2 and Bruton’s tyrosine kinase synergize to abrogate diffuse large B-cell lymphoma (DLBCL) growth

Project description:Methods: DLBCL cell lines RIVA, U-2932 and OCI-LY3 were treated in vitro with ibrutinib (Ibru) or dimethyl sulfoxide (DMSO). Additionally, RIVA and U-2932 were orthotopically transplanted into MISTRG mice and mice were treated for two weeks with Ibru or vehicle. Tumor cells were isolated from the bone marrow at the study endpoint. The total RNA was isolated and the mRNA profiles were generated by next-generation sequencing using the Illumina TruSeq mRNA stranded protocol. Results: We have combined single and combinatorial drug response profiling to show that the combined inhibition of the anti-apoptotic protein Bcl-2 and of the tyrosine kinase BTK with the small molecules venetoclax and ibrutinib efficiently kills DLBCL cells. High Bcl-2 expression due to either BCL2 amplifications or translocations, in conjunction with chronic active BCR signalling accurately predict responses to dual Bcl-2/BTK inhibition.The combined data show that drug sensitivities exposed by drug response profiling can be attributed to specific mutational signatures and immunohistochemical biomarkers, and point to combined Bcl-2/BTK inhibition as a novel promising therapeutic strategy in DLBCL.

2022-01-24 | GSE171763 | GEO

Targeting mitochondrial structure sensitizes AML to Venetoclax

Project description:Targeting mitochondrial structure sensitizes AML to Venetoclax

| PRJNA516226 | ENA

Bruton's tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax.

Project description:Disparate pathogenic mechanisms complicate precision-medicine efforts to treat diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis. Though potentially curable with frontline combination chemoimmunotherapy, DLBCL carries persistently poor prognosis for those with relapsed or refractory (rel/ref) disease, despite recent advances in immunotherapy. Here, we build on recent findings implicating gain-of-function mutations in the BCL10 signaling protein as drivers of resistance to Bruton's tyrosine kinase (BTK) inhibitors. We show mutant BCL10-driven DLBCL is resistant to multiple additional drug classes, demonstrating urgency to derive mechanistically rooted strategies to overcome undruggable BCL10 mutants that stabilize BTK-independent signaling filaments upstream of NF-kB activation. BCL10 mutants promote a cytokine-reinforced positive feedback loop of lymphomagenesis driving not just NF-kB but multiple additional pathways converging on diffuse activation of oncogenic transcription factors. Up-regulation of anti-apoptotic genes increases mitochondrial membrane potential, underlying multidrug resistance. Increased expression of BCL2, BCL2L1 (BCL-XL), and BCL2A1 (BFL1) drives resistance to venetoclax, but expression can be overcome by the potent non-covalent BTK inhibitor pirtobrutinib. Venetoclax plus pirtobrutinib synergized in overcoming resistance and potently killed BCL10-mutant lymphomas in vitro and in vivo. BTK therefore retains key roles protecting DLBCL from apoptosis even when downstream activation of the BCL10 signaling complex activates NF-kB independently.

| S-EPMC11788437 | biostudies-literature

Targeting SUMOylation sensitizes Acute myeloid leukemia to Venetoclax treatment

Project description:Targeting SUMOylation sensitizes Acute myeloid leukemia to Venetoclax treatment

| PRJNA1113589 | ENA

Inhibitors of Bcl-2 and Bruton’s tyrosine kinase synergize to abrogate diffuse large B-cell lymphoma (DLBCL) growth

Project description:Inhibitors of Bcl-2 and Bruton’s tyrosine kinase synergize to abrogate diffuse large B-cell lymphoma (DLBCL) growth

| PRJNA720831 | ENA

Splicing modulation increases BCL2 dependence and sensitizes Multiple Myeloma cells to Venetoclax

Project description:Splicing modulation increases BCL2 dependence and sensitizes Multiple Myeloma cells to Venetoclax

| PRJNA702777 | ENA

DLBCL

Project description:DLBCL

| PRJNA1118307 | ENA

Expression data from DLBCL tumor biopsies

Project description:Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton’s tyrosine kinase (BTK)–mediated B-cell receptor (BCR) signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance. Ibrutinib-resistant TMD8 cells had higher BCL2 gene expression and increased sensitivity to ABT-199, a BCL-2 inhibitor. Consistently, clinical samples from ABC-DLBCL patients who experienced poorer response to ibrutinib had higher BCL2 gene expression. We further demonstrated synergistic growth suppression by ibrutinib and ABT-199 in multiple ABC-DLBCL, GCB-DLBCL, and FL lymphoma cell lines. The combination of both drugs also reduced colony formation, increased apoptosis, and inhibited tumor growth in a TMD8 xenograft model. A synergistic combination effect was also found in ibrutinib-resistant cells generated by either genetic mutation or drug treatment. Together, these findings suggest a potential clinical benefit from ibrutinib and ABT-199 combination therapy.

2017-04-30 | GSE93984 | GEO

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