Reduced EGFR and increased miR-221 is associated with increased resistance to temozolomide and radiotherapy in glioblastoma

Areeb, Zammam; Stuart, Sarah F.; West, Alice J.; Gomez, Juliana; Nguyen, Huy; Paradiso, Lucy; Zulkifli, Ahmad; Jones, Jordan; Kaye, Andrew H.; Morokoff, Andrew; Luwor, Rodney B.

doi:10.1038/s41598-020-74746-x

Cited by 22 publications

(12 citation statements)

References 53 publications

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“…Among the 42 genes (Supplementary Table 6), we identified several genes involved in the TMZ response that are worth mentioning. The EGFR gene, which showed a significant downregulation in Non-Resp samples, is consistent with literature data showing that glioblastoma TMZ-resistant cell lines lack EGFR activation and expression (30). Our results are, as well, confirmed for the upregulation of the CA9 gene in the Non-Resp group, the inhibition of which enhances the sensitivity of glioma cells to TMZ treatment, and highlights the value of developing small molecules or antibodies against the CA9 pathway, for combination therapy with TMZ (31) (Supplementary Table 9; Figure 5A).…”

Section: Whole Transcriptome Analysis (Wta)supporting

confidence: 91%

Metabolic-imaging of human glioblastoma live tumors: A new precision-medicine approach to predict tumor treatment response early

et al. 2022

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BackgroundGlioblastoma (GB) is the most severe form of brain cancer, with a 12-15 month median survival. Surgical resection, temozolomide (TMZ) treatment, and radiotherapy remain the primary therapeutic options for GB, and no new therapies have been introduced in recent years. This therapeutic standstill is primarily due to preclinical approaches that do not fully respect the complexity of GB cell biology and fail to test efficiently anti-cancer treatments. Therefore, better treatment screening approaches are needed. In this study, we have developed a novel functional precision medicine approach to test the response to anticancer treatments in organoids derived from the resected tumors of glioblastoma patients.MethodsGB organoids were grown for a short period of time to prevent any genetic and morphological evolution and divergence from the tumor of origin. We chose metabolic imaging by NAD(P)H fluorescence lifetime imaging microscopy (FLIM) to predict early and non-invasively ex-vivo anti-cancer treatment responses of GB organoids. TMZ was used as the benchmark drug to validate the approach. Whole-transcriptome and whole-exome analyses were performed to characterize tumor cases stratification.ResultsOur functional precision medicine approach was completed within one week after surgery and two groups of TMZ Responder and Non-Responder tumors were identified. FLIM-based metabolic tumor stratification was well reflected at the molecular level, confirming the validity of our approach, highlighting also new target genes associated with TMZ treatment and identifying a new 17-gene molecular signature associated with survival. The number of MGMT gene promoter methylated tumors was higher in the responsive group, as expected, however, some non-methylated tumor cases turned out to be nevertheless responsive to TMZ, suggesting that our procedure could be synergistic with the classical MGMT methylation biomarker.ConclusionsFor the first time, FLIM-based metabolic imaging was used on live glioblastoma organoids. Unlike other approaches, ex-vivo patient-tailored drug response is performed at an early stage of tumor culturing with no animal involvement and with minimal tampering with the original tumor cytoarchitecture. This functional precision medicine approach can be exploited in a range of clinical and laboratory settings to improve the clinical management of GB patients and implemented on other cancers as well.

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Section: Whole Transcriptome Analysis (Wta)supporting

confidence: 91%

Metabolic-imaging of human glioblastoma live tumors: A new precision-medicine approach to predict tumor treatment response early

et al. 2022

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“…Among the 42 genes (Table 6S), we identified several genes involved in the TMZ response that are worth mentioning. The EGFR gene, which showed a significant downregulation in Non-Resp samples, is consistent with literature data showing that glioblastoma TMZ-resistant cell lines lack EGFR activation and expression 30 . Our results are, as well, confirmed for the upregulation of the CA9 gene in the Non-Resp group, the inhibition of which enhances the sensitivity of glioma cells to TMZ treatment, and highlights the value of developing small molecules or antibodies against the CA9 pathway, for combination therapy with TMZ 31 (Table 9S, Fig 5a).…”

Section: Resultssupporting

confidence: 91%

Metabolic-imaging of human glioblastoma live tumors: a new precision-medicine approach to predict tumor treatment response early

Morelli

Lessi

Barachini

et al. 2022

Preprint

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Background: Glioblastoma (GB) is the most severe form of brain cancer, with a 12-15 month median survival. Surgical resection, temozolomide (TMZ) and radiotherapy (RT) remain the primary therapeutic options for GB, and no new therapies have been introduced in recent years. This therapeutic standstill is primarily due to preclinical models that do not reflect the complexity of GB cell biology and fail to test anti-cancer treatments valuably. Better preclinical models for compound screening are therefore needed. Methods: In-vitro 3D glioblastoma live explants (GB-EXPs) were derived from patients′ resected tumors. We then applied metabolic imaging by fluorescence lifetime imaging microscopy (FLIM) on to GB-EXPs to assess drug response, using TMZ as our benchmark drug. Whole-transcriptome and whole-exome analyses were performed. Results: Using FLIM we were able to stratify samples in Responder and Non-Responder tumors. Our functional precision medicine approach was successfully completed within 1 week of surgery. FLIM-based tumor samples stratification was well reflected at the molecular level, highlighting new targets associated with TMZ treatment and identifying a molecular signature associated with survival. Conclusions: To the best of our knowledge, this is the first time that FLIM-based metabolic imaging is used on live glioblastoma 3D explants to test anti-neoplastic drugs rapidly. FLIM-based readouts of drug response in GB explants could improve precision treatment of patients with GB and the identification of new anti-GB drugs.

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“…The present study found a lowered expression of EGFR in drugresistant, quiescent CSCs derived from TMZ-R tumors. Our findings corroborate EGFR expression and activity patterns observed in several TMZ-resistant cell lines and GBM patient tumor tissues [51]. For example, Areeb et al report that in addition to deficient EGFR expression in treatment-resistant cells, there is significant upregulation of the EGFR-targeting miR-221, which likely serves as a mechanism of reduced EGFR expression.…”

Section: Discussionsupporting

confidence: 88%

Characterization of EGFR-reprogrammable temozolomide-resistant cells in a model of glioblastoma

Gong

Yin

Chen

et al. 2022

Preprint

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Temozolomide (TMZ) resistance is a major clinical challenge for glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) mediated DNA damage repair is a key mechanism for TMZ resistance. However, MGMT-null GBM patients remain resistant to TMZ, and the process for resistance evolution is largely unknown. Here, we developed an acquired TMZ resistant xenograft model using serial implantation of MGMT-null U87 cells, allowing the extraction of stable, TMZ resistant (TMZ-R) tumors and primary cells. The derived tumors and cells exhibited stable multidrug resistance both in vitro and in vivo. Functional experiments, as well as single-cell RNA sequencing (scRNA-seq), indicated that TMZ treatment induced cellular heterogeneity including quiescent cancer stem cells (CSCs) in TMZ-R tumors. A subset of these were labeled by NES+/SOX2+/CADM1+ and demonstrated significant advantages for drug resistance. Further study revealed that Epidermal Growth Factor Receptor (EGFR) deficiency and diminished downstream signaling may confer this triple positive CSCs subgroup’s quiescent phenotypes and chemoresistance. Continuous EGF treatment improved the chemosensitivity of TMZ-R cells both in vitro and in vivo, mechanically reversing cell cycle arrest and reduced drug uptake. Further, EGF treatment of TMZ-R tumors favorably normalized the response to TMZ in combination therapy. Here, we characterize a unique subgroup of CSCs in MGMT-null experimental glioblastoma, identifying EGF + TMZ therapy as a potential strategy to overcome cellular quiescence and TMZ resistance, likely endowed by deficient EGFR signaling.

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Reduced EGFR and increased miR-221 is associated with increased resistance to temozolomide and radiotherapy in glioblastoma

Cited by 22 publications

References 53 publications

Metabolic-imaging of human glioblastoma live tumors: A new precision-medicine approach to predict tumor treatment response early

Metabolic-imaging of human glioblastoma live tumors: A new precision-medicine approach to predict tumor treatment response early

Metabolic-imaging of human glioblastoma live tumors: a new precision-medicine approach to predict tumor treatment response early

Characterization of EGFR-reprogrammable temozolomide-resistant cells in a model of glioblastoma

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