RAPID RESISTANCE TO BET INHIBITORS IS MEDIATED BY FGFR1 IN GLIOBLASTOMA
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1029178 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26412972_1.fastq.gz | Fastqsanger.gz | |||
| SRR26412972_2.fastq.gz | Fastqsanger.gz | |||
| SRR26412973_1.fastq.gz | Fastqsanger.gz | |||
| SRR26412973_2.fastq.gz | Fastqsanger.gz | |||
| SRR26412974_1.fastq.gz | Fastqsanger.gz |
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Project description:Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.
2024-06-16 | PXD043214 | Pride
Project description:Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that intrinsic resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Additionally, small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.
2023-10-23 | GSE245624 | GEO
Project description:Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of sensitive cells. Bioinformatic analyses showed that JQ1-sensitive cells could also respond to Aurora Kinase A inhibition which indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibition could potentiate the efficacy of TMZ or could be combined with Aurora Kinase inhibitors in MYCN-elevated GBM.
2019-12-05 | GSE138942 | GEO
Project description:Human glioblastoma cell lines L0, L1, L2 (Deleyrolle et al. Brain 2010) were transduced with lentivirus vectors expressing scrambled control (shCo), FGFR1 knockdown (shFGFR1), or FGFR2 knockdown (shFGFR2) sequences. Cells were cultured in N2 medium containing EGF and stimulated with FGF2 for 48 hours prior to RNA extraction.
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Project description:BET and Aurora Kinase A Inhibitors Synergize against MYCN-positive Human Glioblastoma Cells
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Project description:Recently, FGFR1 has been found to be overexpressed in osteosarcoma and thus represents an important target for precision medicine. However, because targeted cancer therapy based on FGFR inhibitors has so far been less efficient than expected, a detailed understanding of the target is important. We have here applied proximity labelling of FGFR1 in an osteosarcoma cell line to identify determinants of FGFR1 activity. Many known FGFR interactors were identified (e.g. FRS2, PLC, RSK2, SHC4, SRC), but the data also suggested novel determinants. A strong hit in our screen was the tyrosine phosphatase PTPRG. We show that PTPRG and FGFR1 interact and colocalize at the plasma membrane where PTPRG directly dephosphorylates activated FGFR1. We further show that osteosarcoma cell lines depleted for PTPRG display increased FGFR activity and are hypersensitive to stimulation by FGF1. In addition, PTPRG depletion elevated cell growth and negatively affected the efficacy of FGFR kinase inhibitors. Thus, PTPRG may have future clinical relevance by being a predictor of outcome after FGFR inhibitor treatment.
2018-01-29 | PXD006157 | Pride
Project description:The BET (bromodomain and extra-terminal) family of acetyl-lysine reader proteins acts as transcriptional activators. BET inhibitors showed anti-cancer efficacies. We performed microarray analysis to characterize BET inhibitor-induced gene expression alterations.
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Project description:Gene expression data for BET inhibitors
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Project description:Small molecule BET bromodomain inhibitors (BETi) are actively being pursued in clinical trials for the treatment of a variety of cancers, however, the mechanisms of resistance to targeted BET protein inhibitors remain poorly understood. Using a novel mass spectrometry approach that globally measures kinase signaling at the proteomic level, we evaluated the response of the kinome to targeted BET inhibitor treatment in a panel of BRD4-dependent ovarian carcinoma (OC) cell lines. Despite initial inhibitory effects of BETi, OC cells acquired resistance following sustained treatment with the BETi, JQ1. Through application of Multiplexed Inhibitor Beads (MIBs) and mass spectrometry, we demonstrate that BETi resistance is mediated by adaptive kinome reprogramming, where activation of compensatory pro-survival kinase networks overcomes BET protein inhibition. Furthermore, drug combinations blocking these kinases may prevent or delay the development of drug resistance and enhance the efficacy of BET inhibitor therapy. RNAseq was employed to identify changes in kinase RNA expression following short term (48h) or chronic (JQ1R) JQ1 treatment in three different ovarian cancer cell lines.
2016-07-21 | E-GEOD-82329 | biostudies-arrayexpress
Project description:Nowadays, fibroblast growth factor receptor 1 (FGFR1) inhibitors are considered as an effective kinase inhibitor for 8p11 myeloproliferative syndrome (EMS) treatment. However, targeting FGFR1 alone may not be sufficient in EMS patients with TPR-FGFR1 rearrangement. In this study, we established TPR FGFR1 expressing Baf3 cells and performed RNA-Seq analysis. RNA-Seq analysis revealed that genes associated with TPR-FGFR1 expression mainly participated in the epidermal growth factor receptor (EGFR) pathway (|FC| > 1.80, P < 0.05). Gene set enrichment analysis (GSEA) identified significant enrichment in the PI3K/AKT pathways. We found that EGFR is another activation pathway for AKT in TPR-FGFR1-expressing Baf3 cells. Moreover, we found that treatment with FGFR1 inhibitors alone could completely inhibit FGFR1 phosphorylation, but could not completely inhibit AKT, which is the downstream molecule of FGFR1. Compared to FGFR1 inhibitors alone, co-treatment with PD-166866 (FGFR1 inhibitor) and MK-2206 (AKT inhibitor) could simultaneously inhibit the phosphorylation of FGFR1 and AKT. In addition, FACS results indicated that the combination therapy of PD-168866 and MK-2206 significantly increased the rate of cells apoptosis than monotherapy of PD-166866 (P < 0.0001). Collectively, the data obtained in the present study provides strong evidence for dual targeting therapy of FGFR1 and AKT in EMS patients with TPR-FGFR1 rearrangement, offering a new direction for EMS treatment.
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