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MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

ABSTRACT: Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas1. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients2. Here we show that a subset of recurrent gliomas carry MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that they lead to TMZ resistance both in vitro and in vivo. Lastly we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

PROVIDER: EGAS00001004544 | EGA |

REPOSITORIES: EGA

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661b1868-1ffa-4101-a0ac-6eed395c92db - samples

Project description:Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carry MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that they lead to TMZ resistance both in vitro and in vivo. Lastly we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

| EGAD00001006281 | EGA

Drug resistance in glioblastoma

Project description:Combined model of in vitro and in vivo resistance to alkylating agents (BCNU and Temozolomide) in glioblastoma multiforme. Three matched pairs of surgical specimens from initial (DI, ME, LX) and repeat (DIR, MER, LXR) tumor resection were used to establish cell lines. Patients received BCNU chemotherapy between the two operations, which rendered the sublines from repeat surgery more resistant to BCNU than those from initial surgery. Each the pre-chemotherapeutic set and the post-chemotherapeutic set of cell lines was selected in vitro for resistance to either BCNU or Temozolomide. 9 in vitro selected sublines were established. Of those 4 (2 selected for BCNU [ME-BCNU, DI-BCNU] and 2 selected for Temozolomide [ME-TMZ, LX-TMZ) were generated from the parental/sensitive pre-chemotherapeutic set and 5 (2 selected for BCNU [DIR-BCNU, MER-BCNU] and 3 selected for Temozolomide [DIR-TMZ, MER-TMZ, LXR-TMZ) from the in vivo resistant post-chemotherapeutic set. The model included a total of 15 sublines. Genome-wide high-resolution gene copy number profiling was performed on each subline using 42,000-feature cDNA microarrays. Utilizing the same microarray platform genome-wide gene expression profiles were generated. Biostatistical tools were employed to identify signatures of resistance to alkylating agents both at the genetic as well as at the transcriptomic levels. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Series_type = Logical Set Keywords: other

2006-01-27 | GSE2221 | GEO

Class I HDAC overexpression promotes temozolomide resistance in glioma cells by regulating RAD18 expression

Project description:Overexpression of histone deacetylases (HDACs) in cancer commonly causes resistance to genotoxic based therapies. Here we report on the novel mechanism whereby overexpressed class I HDACs increase the resistance of glioblastoma cells to the SN1 methylating agent temozolomide (TMZ). The chemotherapeutic TMZ triggers the activation of the DNA damage response (DDR) in resistant glioma cells, leading to DNA lesion bypass and cellular survival. Mass spectrometry analysis revealed that the catalytic activity of class I HDACs stimulates the expression of the E3 ubiquitin ligase RAD18. Furthermore, the data show that RAD18 is part of the O6-methylguanine-induced DDR as TMZ induces the formation of RAD18 foci at sites of DNA damage. Downregulation of RAD18 by HDAC inhibition prevents glioma cells from activating the DDR upon TMZ exposure. Lastly, RAD18 or O6-methylguanine-DNA methyltransferase (MGMT) overexpression abolishes the sensitization effect of HDAC inhibition on TMZ-exposed glioma cells. Our study describes the mechanism whereby class I HDAC overexpression in glioma cells causes resistance to TMZ treatment. HDACs accomplish this by promoting the bypass of O6-methylguanine DNA lesions via enhancing RAD18 expression. It also provides a treatment option with HDAC inhibition to undermine this mechanism.

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2011-01-08 | E-TABM-890 | biostudies-arrayexpress

Cytoplasmic Proteomics for Temozolomide Resistance in Glioblastoma

Project description:TMZ resistance is one of the main reasons why treatment of glioblastoma (GBM) fails. In order to investigate the underlying mechanism associated with TMZ resistance, we conducted a cytoplasmic proteome research of U87 cells treated with TMZ for 1 week. A total of 162 DEPs including 66 up-regulated proteins and 96 down-regulated proteins were identified.

2018-10-23 | PXD007759 | Pride

Project description:markers of glioblastoma TMZ resistance

| PRJNA479416 | ENA

Invadopodia small extracellular vesicles glioblastoma

Project description:The therapeutic efficacy of radiotherapy and chemotherapy with temozolomide (TMZ) for glioblastoma (GBM) is currently limited by the augmented invasive abilities of GBM cells that survive treatment, however the underlying mechanisms remain poorly understood. Due to their ability of transporting oncogenic material between cells, small extracellular vesicles (sEVs) have emerged as key mediators of tumour progression and resistance to treatment. Here, we report that sEVs secreted by GBM cells may facilitate tumour invasion through their ability to promote the formation and activity of actin-rich protrusions known as invadopodia, and that this may be further enhanced following exposure to radio-chemotherapeutic treatment. Furthermore, proteomic analysis of GBM cells exposed to this treatment revealed an increased abundance of invasion-related proteins (including adhesion, cytoskeletal, and membrane trafficking proteins), whilst sEVs were instead enriched in invadopodia-related signalling cargo proteins. Collectively, this work highlights the contributing role of invadopodia and sEVs to the pro-invasive abilities of GBM cells that survive radio-chemotherapeutic treatment.

2023-07-24 | PXD031077 | Pride

Multi-omics Analyses Reveal Mitochondrial Dysfunction Con-tributing to Temozolomide Resistance in Glioblastoma Cells

Project description:Glioblastoma (GBM) is the most common and aggressive malignant brain tumor with poor prognosis. Temozolomide (TMZ) is the standard chemotherapy for glioblastoma treatment, but TMZ resistance significantly compromises its efficacy. In the present study, we generated a TMZ-resistant cell line and identified that mitochondrial dysfunction was a novel factor contrib-uting to TMZ resistance though multi-omics analyses and energy metabolism analysis. Further-more, we found that rotenone treatment induced TMZ resistance to a certain level in glioblastoma cells. Notably, we further demonstrated that elevated Ca2+ levels and JNK–STAT3 pathway activa-tion contributed to TMZ resistance and that inhibiting JNK or STAT3 increases susceptibility to TMZ. Taken together, our results indicate that co-administering TMZ with a JNK or STAT3 inhibi-tor holds promise as a potentially effective treatment for glioblastoma.

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Project description:Glioblastoma multiforme(GBM) is the most common and lethal malignant primary brain tumor. Temozolomide (TMZ) is a promising chemo-therapeutic agent to treat GBM. However, resistance to TMZ develops quickly with a high frequency. The mechanisms underlying GBM cells’ resistance to TMZ are not fully understood. Non-coding RNAs are aberrantly expressed in many cancers and are highly involved in their pathogenesis including drug-resistence. In order to systematically study the role of miRNAs in GBM cells' resistence to TMZ , we built gene expression profiles of TMZ-resistant cell line and TMZ-sensitive cell line using miRNA gene expression microarrays.

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