RNA-Seq study of Cell lines rendered resistant to idelalisib and ibrutinib
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA486519 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7706484_1.fastq.gz | Fastqsanger.gz | |||
| SRR7706484_2.fastq.gz | Fastqsanger.gz | |||
| SRR7706485_1.fastq.gz | Fastqsanger.gz | |||
| SRR7706485_2.fastq.gz | Fastqsanger.gz | |||
| SRR7706486_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:BCR pathway inhibitors idelalisib and ibrutinib are the first small molecule targeted agents for B-cell malignancies. In spite of encouraging response rates in various forms of B cell diseases, patients will eventually develop relapse due to the emergence of resistant cells. To better identify the possible mechanisms of resistance we developed and characterized idelalisib- and ibrutinib-resistant variants of the human non Hodgkin’s lymphoma cell lines DoHH2 and Daudi. These resistant variants displayed a cross-resistance profile limited to PI3K inhibitors, BTK inhibitors and a SYK inhibitor but not to unrelated agents. A number of alterations were observed in the resistant lines, including a strong reduction of the Akt3 protein. Resistant lines tended to express larger amounts of CD38 and CD52 on their cell membrane and were found to display enhanced sensitivity to anti-CD38 antibodies. These results identify potential novel mechanisms of resistance to idelalisib and ibrutinib and raise the possibility that cells resistant to BCR pathway inhibitors might possess enhanced sensitivity to anti-CD38 antibodies.
2019-08-19 | GSE118707 | GEO
Project description:Idelalisib was the first-in-class PI3Kδ inhibitor and additional compounds are undergoing clinical investigation. To identify modalities to overcome resistance to these agents, we have developed idelalisib-resistant model derived from marginal zone lymphoma cell line (VL51). Cells were kept under idelalisib until acquisition of resistance (VL51-RER) or with no drug (parental). In this experiment we identified the modulated genes between the resistant cell line and the parental counterpart (sensitive to the drug) We invastigated the transcriptomic profiles of parental K1718 B-cell lymphoma cell lines and the same cell line made resistant to Idelalisib. in addition two B-Cells (SUDHL2 and SUDHL4) are made resistant to IMGN529 (Naratuximab emtansine) an antibody-drug conjugate (ADC) incorporating an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload.
2024-05-06 | GSE173984 | GEO
Project description:Treatment of MEC1, EHEB and JVM2 leukemia cell lines with fludarabine, ibrutinib and idelalisib
| PRJNA557198 | ENA
Project description:RNAseq profile of TMD8 cell lines resistant to Idelalisib treatment. Idelalisib resistant TMD8 cells were generated by continuous passage in the presence of 1 μM idelalisib for 8 weeks until stable resistance to idelalisib was established. Parallel cultures were grown in the presence of 0.1% DMSO as passage-matched, drug-sensitive control lines. Sensitive and resistant TMD8 cells were clonally isolated through two rounds of single cell limiting dilution
2017-02-17 | GSE93156 | GEO
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 | GSE93985 | GEO
Project description:We established two representative ABC DLBCL cell lines (TMD8 and OCI-Ly10) with ibrutinib resistance by gradually increasing the concentration of ibrutinib during passage in culture. RNA-seq analysis demonstrated that the BCR pathway gene signature is enriched in resistant cell lines when compared to parental cells. The most upregulated gene is EGR1, a transcription factor that activates multiple oncogenic pathways including MYC and E2F. Elevated EGR1 expression is also observed in ibrutinib-resistant primary mantle cell lymphoma cells when treated with ibrutinib. Using multiple metabolic and genetic approaches, we discovered that overexpression of EGR1 causes metabolic reprogramming to oxidative phosphorylation (OXPHOS) and ibrutinib resistance. Mechanistically, EGR1 mediates metabolic reprogramming through transcriptional activation of PDP1, a phosphatase that dephosphorylates and activates the E1 component of the large pyruvate dehydrogenase complex. Therefore, EGR1-mediated PDP1 activation accelerates intracellular ATP production via the mitochondrial tricarboxylic acid (TCA) cycle, leading to sufficient energy to enhance the proliferation and survival of ibrutinib-resistant lymphoma cells. Finally, we demonstrate that targeting OXPHOS with IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in patient-derived xenograft mouse models.
2023-12-06 | GSE223150 | GEO
Project description:RNA-Seq of B-Cell Lines Clones, parental and resistant to Idelalisib or IMGN529
| PRJNA727808 | ENA
Project description:To determine the global transcriptome changes in mantle cell lymphoma cells following treatment with the BET bromodomain antagonist, JQ1 Mantle Cell Lymphoma (MCL) cells exhibit increased B cell receptor and NFkB activities. The BET protein BRD4 is essential for the transcriptional activity of NFkB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and CDK4/6, inhibits the nuclear RelA levels and the expression of NFκB target genes including Brutonâs Tyrosine Kinase (BTK) in MCL cells. While lowering the levels of the anti-apoptotic BCL2 family proteins, BA treatment induces the pro-apoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Co-treatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared to each agent alone, co-treatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells which overexpress CDK6, BCL2, Bcl-xL, XIAP and AKT, but lack ibrutinib resistance-conferring BTK mutation. Co-treatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL. MO2058 cells treated with vehicle, 250 nM or 1000 nM JQ1 for 8 hours. Samples were acquired and analyzed in duplicate.
2015-12-31 | E-GEOD-70651 | biostudies-arrayexpress
Project description:The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease. Cancer Res; 77(24); 7038-48. ©2017 AACR.
2018-04-03 | GSE98206 | GEO
Project description:Most BRAF-mutant melanoma tumors respond initially to BRAFi/MEKi therapy, although few patients have durable long-term responses to these agents. The goal of this study was to utilize an unbiased computational approach to identify inhibitors which reverse an experimentally derived BRAFi resistance gene expression signature. Using this approach, we predicted that ibrutinib, a BTK inhibitor, effectively reverses this signature, and we demonstrate experimentally that ibrutinib re-sensitizes a subset of BRAFi-resistant melanoma cells to vemurafenib. Ibrutinib is used clinically as a BTK inhibitor; however, neither BTK deletion nor treatment with acalabrutinib, an analog of ibrutinib with reduced off-target activity, re-sensitized cells to vemurafenib. These data suggest that ibrutinib acts through a BTK-independent mechanism in vemurafenib re-sensitization. To better understand this mechanism, we analyzed the transcriptional profile of ibrutinib-treated BRAFi-resistant melanoma cells and found that the transcriptional profile of ibrutinib was highly similar to that of multiple SRC kinase inhibitors. Since ibrutinib, but not acalabrutinib, has significant off-target activity against multiple SRC family kinases, it suggests that ibrutinib may be acting through this mechanism. Furthermore, genes either upregulated or downregulated by ibrutinib treatment are enriched with YAP1 target genes and we experimentally demonstrate that ibrutinib, but not acalabrutinib, reduces YAP1 activity in BRAFi-resistant melanoma cells. Taken together, these data suggest that ibrutinib, or other SRC family kinase inhibitors, may be useful for treating some BRAFi/MEKi-refractory melanoma tumors.
2020-02-27 | GSE145990 | GEO