Molecular Mechanisms of Drug Resistance in Glioblastoma

Дымова, М. А.; Kuligina, Elena V.; Richter, Vladimír

doi:10.3390/ijms22126385

Cited by 65 publications

(45 citation statements)

References 128 publications

(139 reference statements)

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“…The predominant effect of ionizing radiation (IR) and DNA-targeted chemotherapy on cancer cells is the induction of DNA damage of which DNA double-strand breaks are most severe, ultimately leading to cell cycle arrest, cell death, and abrogation of clonogenic survival [ 23 ]. Accordingly, resistance against DNA damage-induced cell death and clonogenic inactivation is a major obstacle in current GBM treatment [ 24 ], and frequently derives from alterations both in abundance and functionality of DNA damage response (DDR) regulators [ 25 ]. In the present study, we examined the basal mRNA expression levels of 38 DDR genes in a panel of seven human GBM cell lines in comparison to primary human astrocytes and observed a thorough and massive upregulation of multiple DDR genes analyzed (Fig.…”

Section: Resultsmentioning

confidence: 99%

Integrative analysis of therapy resistance and transcriptomic profiling data in glioblastoma cells identifies sensitization vulnerabilities for combined modality radiochemotherapy

et al. 2022

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Background Inherent resistance to radio/chemotherapy is one of the major reasons for early recurrence, treatment failure, and dismal prognosis of glioblastoma. Thus, the identification of resistance driving regulators as prognostic and/or predictive markers as well as potential vulnerabilities for combined modality treatment approaches is of pivotal importance. Methods We performed an integrative analysis of treatment resistance and DNA damage response regulator expression in a panel of human glioblastoma cell lines. mRNA expression levels of 38 DNA damage response regulators were analyzed by qRT-PCR. Inherent resistance to radiotherapy (single-shot and fractionated mode) and/or temozolomide treatment was assessed by clonogenic survival assays. Resistance scores were extracted by dimensionality reduction and subjected to correlation analyses with the mRNA expression data. Top-hit candidates with positive correlation coefficients were validated by pharmacological inhibition in clonogenic survival assays and DNA repair analyses via residual γH2AX/53BP1-foci staining. Results Inherent resistance to single-shot and similarly also to fractionated radiotherapy showed strong positive correlations with mRNA expression levels of known vulnerabilities of GBM, including PARP1, NBN, and BLM, as well as ATR and LIG4—two so far underestimated targets. Inhibition of ATR by AZD-6738 resulted in robust and dose-dependent radiosensitization of glioblastoma cells, whereas LIG4 inhibition by L189 had no noticeable impact. Resistance against temozolomide showed strong positive correlation with mRNA expression levels of MGMT as to be expected. Interestingly, it also correlated with mRNA expression levels of ATM, suggesting a potential role of ATM in the context of temozolomide resistance in glioblastoma cells. ATM inhibition exhibited slight sensitization effects towards temozolomide treatment in MGMT low expressing glioblastoma cells, thus encouraging further characterization. Conclusions Here, we describe a systematic approach integrating clonogenic survival data with mRNA expression data of DNA damage response regulators in human glioblastoma cell lines to identify markers of inherent therapy resistance and potential vulnerabilities for targeted sensitization. Our results provide proof-of-concept for the feasibility of this approach, including its limitations. We consider this strategy to be adaptable to other cancer entities as well as other molecular data qualities, and its upscaling potential in terms of model systems and observational data levels deserves further investigation.

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Section: Resultsmentioning

confidence: 99%

Integrative analysis of therapy resistance and transcriptomic profiling data in glioblastoma cells identifies sensitization vulnerabilities for combined modality radiochemotherapy

et al. 2022

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“…The authors demonstrated that TMZ (at therapeutic concentration) increased the transport of Pgp substrates across human brain microvascular endothelial cells and decreased the expression of Pgp. The scenario is much more complex for the blood-brain tumor barrier (BBTB), which reflects the complex regional heterogeneity of immune cell populations compared to the BBB [33]. The BBTB is generally considered 'leakier' than the BBB, which is characterized by aberrant pericyte distribution and loss of astrocytic endfeet and neuronal connections [34,35].…”

Section: Landscapes Of Unique Immune Suppression In Glioblastomamentioning

confidence: 99%

“…The scenario is much more complex for the blood-brain tumor barrier (BBTB), which reflects the complex regional heterogeneity of immune cell populations compared to the BBB [33]. The BBTB is generally considered 'leakier' than the BBB, which is characterized by aberrant pericyte distribution and loss of astrocytic endfeet and neuronal connections [34,35].…”

Section: Landscapes Of Unique Immune Suppression In Glioblastomamentioning

confidence: 99%

Recent Development in NKT-Based Immunotherapy of Glioblastoma: From Bench to Bedside

Sharma

Maciaczyk

et al. 2022

IJMS

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Glioblastoma multiforme (GBM) is an aggressive and dismal disease with a median overall survival of around 15 months and a 5-year survival rate of 7.2%. Owing to genetic mutations, drug resistance, disruption to the blood–brain barrier (BBB)/blood–brain tumor barrier (BBTB), and the complexity of the immunosuppressive environment, the therapeutic approaches to GBM represent still major challenges. Conventional therapies, including surgery, radiotherapy, and standard chemotherapy with temozolomide, have not resulted in satisfactory improvements in the overall survival of GBM patients. Among cancer immunotherapeutic approaches, we propose that adjuvant NKT immunotherapy with invariant NKT (iNKT) and cytokine-induced killer (CIK) cells may improve the clinical scenario of this devastating disease. Considering this, herein, we discuss the current strategies of NKT therapy for GBM based primarily on in vitro/in vivo experiments, clinical trials, and the combinatorial approaches with future therapeutic potential.

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“…These properties could lead to the formation of a heterogeneous landscape not only by malignant cells that differ from each other, depending on their metabolic requirements, but also by the presence of endothelial cells and populations of the innate and adaptive immune system [6,7]. Tumor heterogeneity shaped by genetic and metabolic aberrations as well as by immunoediting mechanisms confers GBM high resistance to drugs, which leads to poor prognosis for the patient [8]. Therefore, the interconnections between two or more malignant cell hallmarks and the revelation of intercellular associations could offer novel insights into cancer biology, as well as promising targets for therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Kynurenine Monooxygenase Expression and Activity in Human Astrocytomas

Cervantes

Pineda

Ortega

et al. 2021

Cells

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Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The enzyme indoleamine-2,3-dioxygenase (IDO), which participates in the rate-limiting step of tryptophan catabolism through the kynurenine pathway (KP), is associated with poor prognosis in patients with GBM. The metabolites produced after tryptophan oxidation have immunomodulatory properties that can support the immunosuppressor environment. In this study, mRNA expression, protein expression, and activity of the enzyme kynurenine monooxygenase (KMO) were analyzed in GBM cell lines (A172, LN-18, U87, U373) and patient-derived astrocytoma samples. KMO mRNA expression was assessed by real-time RT-qPCR, KMO protein expression was evaluated by flow cytometry and immunofluorescence, and KMO activity was determined by quantifying 3-hydroxykynurenine by HPLC. Heterogenous patterns of both KMO expression and activity were observed among the GBM cell lines, with the A172 cell line showing the highest KMO expression and activity. Higher KMO mRNA expression was observed in glioma samples than in patients diagnosed with only a neurological disease; high KMO mRNA expression was also observed when using samples from patients with GBM in the TCGA program. The KMO protein expression was localized in GFAP+ cells in tumor tissue. These results suggest that KMO is a relevant target to be explored in glioma since it might play a role in supporting tumor metabolism and immune suppression.

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Molecular Mechanisms of Drug Resistance in Glioblastoma

Cited by 65 publications

References 128 publications

Integrative analysis of therapy resistance and transcriptomic profiling data in glioblastoma cells identifies sensitization vulnerabilities for combined modality radiochemotherapy

Integrative analysis of therapy resistance and transcriptomic profiling data in glioblastoma cells identifies sensitization vulnerabilities for combined modality radiochemotherapy

Recent Development in NKT-Based Immunotherapy of Glioblastoma: From Bench to Bedside

Kynurenine Monooxygenase Expression and Activity in Human Astrocytomas

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