Inhibitors of Bcl-2 and Bruton’s tyrosine kinase synergize to abrogate diffuse large B-cell lymphoma (DLBCL) growth
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA720831 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14195300.fastq.gz | Fastqsanger.gz | |||
| SRR14195301.fastq.gz | Fastqsanger.gz | |||
| SRR14195302.fastq.gz | Fastqsanger.gz | |||
| SRR14195303.fastq.gz | Fastqsanger.gz | |||
| SRR14195304.fastq.gz | Fastqsanger.gz |
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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
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
Project description:Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors to venetoclax
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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
Project description:The mTOR (mammalian Target of Rapamycin) pathway is constitutively activated in Diffuse Large B-Cell Lymphoma (DLBCL). mTOR inhibition has been shown to have clinical activity in patients with DLBCL, although overall response rates remain low. We therefore evaluated differences in the transcriptome between DLBCL cell lines with differential sensitivity to the mTOR inhibitor Rapamycin, to (A) identify gene-expression patterns(GEP) capable of identifying sensitivity to Rapamycin, (B) understand the underlying mechanisms of resistance to Rapamycin in DLBCL and (C) identify bioactive molecules likely to synergize with mTOR inhibitors. Using Affymetrix HuGene ST 1.0 microarrays, we were able to identify a gene expression signature capable of accurately predicting sensitivity and resistance to Rapamycin in DLBCL cell lines. Pathway analysis identified the serine/threonine kinase Akt as central to the differentially-expressed gene network. Connectivity mapping of our datasets identified compounds targeting the AKT pathway with a high likelihood of reversing the GEP associated with resistance to Rapamycin. Specifically, we evaluated the HIV protease inhibitor (PI) Nelfinavir, which is known to have anti-cancer and Akt-inhibitory properties, as well as the small molecule Akt inhibitor MK-2206, for their potential to synergize with to Rapamycin in DLBCL. Nelfinavir and MK-2206 caused profound inhibition of cell viability in combination with Rapamycin in DLBCL cell lines. Low nanomolar concentrations of Rapamycin inhibited phosphorylation of Akt and also downstream targets of activated mTOR when used in combination with these Akt inhibitors. These findings have the potential to significantly improve patient selection for mTOR inhibitor therapy, and to improve rates and depths of response. More broadly, they support the use of global RNA expression and connectivity mapping to improve patient selection and identify synergistic drug combinations for cancer therapy. DLBCL cell lines were tested for Rapamycin sensitivity and classified as "sensitive" or "resistant." Genome-wide analysis of all cell lines were performed using the Affymetrix HuGene ST 1.0 Array Platform. Genes with differential expression between sensitive and resistant cell lines were analyzed using Statistical Analysis of Microarrays (SAM) software, and a signature of genes determnined. This signature was found to accurately predict sensitivity or resistance of other DLBCL cell lines, and to identify the protein kinase Akt as central to resistance.
2012-04-29 | E-GEOD-27255 | biostudies-arrayexpress
Project description:The mTOR (mammalian Target of Rapamycin) pathway is constitutively activated in Diffuse Large B-Cell Lymphoma (DLBCL). mTOR inhibition has been shown to have clinical activity in patients with DLBCL, although overall response rates remain low. We therefore evaluated differences in the transcriptome between DLBCL cell lines with differential sensitivity to the mTOR inhibitor Rapamycin, to (A) identify gene-expression patterns(GEP) capable of identifying sensitivity to Rapamycin, (B) understand the underlying mechanisms of resistance to Rapamycin in DLBCL and (C) identify bioactive molecules likely to synergize with mTOR inhibitors. Using Affymetrix HuGene ST 1.0 microarrays, we were able to identify a gene expression signature capable of accurately predicting sensitivity and resistance to Rapamycin in DLBCL cell lines. Pathway analysis identified the serine/threonine kinase Akt as central to the differentially-expressed gene network. Connectivity mapping of our datasets identified compounds targeting the AKT pathway with a high likelihood of reversing the GEP associated with resistance to Rapamycin. Specifically, we evaluated the HIV protease inhibitor (PI) Nelfinavir, which is known to have anti-cancer and Akt-inhibitory properties, as well as the small molecule Akt inhibitor MK-2206, for their potential to synergize with to Rapamycin in DLBCL. Nelfinavir and MK-2206 caused profound inhibition of cell viability in combination with Rapamycin in DLBCL cell lines. Low nanomolar concentrations of Rapamycin inhibited phosphorylation of Akt and also downstream targets of activated mTOR when used in combination with these Akt inhibitors. These findings have the potential to significantly improve patient selection for mTOR inhibitor therapy, and to improve rates and depths of response. More broadly, they support the use of global RNA expression and connectivity mapping to improve patient selection and identify synergistic drug combinations for cancer therapy.
2012-04-30 | GSE27255 | GEO
Project description:Diffuse large B cell lymphoma (DLBCL) is the most common aggressive B cell lymphoma and accounts for nearly 40% of cases of B cell non-Hodgkin lymphoma. DLBCL is generally treated with R-CHOP chemotherapy, but many patients do not respond or relapse after treatment. Here, we analyzed the therapeutic potential of the tumor suppressor microRNA-28 (miR-28) for DLBCL, alone and in combination with the Bruton’s tyrosine kinase inhibitor ibrutinib. Combination therapy with miR-28 plus ibrutinib potentiated the anti-tumor effects of monotherapy with either agent by inducing a specific transcriptional cell-cycle arrest program that impairs DNA replication. The molecular actions of miR-28 and ibrutinib synergistically impair DNA replication by simultaneous inhibition of origin activation and fork progression. Moreover, we found that downregulation of the miR-28-plus-ibrutinib gene signature correlates with better survival of ABC-DLBCL patients. These results provide evidence for the effectiveness of a new miRNA-based ibrutinib combination therapy for DLBCL and unveil the miR-28-plus-ibrutinib gene signature as a new predictor of outcome in ABC-DLBCL patients.
2023-09-21 | GSE229786 | GEO
Project description:Multi-agent chemotherapy still represents the first-line standard-of-care treatment for diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adults. However, the clinicopathological and molecular heterogeneity of DLBCLs poses a major challenge in their successful therapy. At least two major subtypes, i.e. germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL, which differ both in their gene expression profile and in their mutation patterns, have been identified. Here we demonstrate a broad inhibitory effect of dimethyl fumarate (DMF) on the outgrowth of both DLBCL subtypes, even though the molecular basis for its efficacy differs between GCB and ABC DLBCL. Due to high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induced lipid peroxidation and thus ferroptotic cell death in GCB DLBCL. In contrast, in ABC DLBCL inhibition of NF-κB and STAT3 activity essentially contributed to DMF-dependent cytotoxicity. Interestingly, the BCL-2 specific BH3 mimetic ABT-199 or an inhibitor of the ferroptosis suppressor protein 1 synergized with DMF treatment in inducing cell death in DLBCL cell lines. Collectively, our findings identify the established and approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCL.
2021-07-01 | GSE164267 | GEO