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

ABSTRACT: Despite aggressive treatment with temozolomide and radiotherapy and extensive research into alternative therapies there has been little improvement in Glioblastoma patient survival. Median survival time remains between 12 and 15 months mainly due to treatment resistance and tumor recurrence. In this study, we aimed to explore the underlying mechanisms behind treatment resistance and the lack of success with anti-EGFR therapy in the clinic. After generating a number of treatment resistant Glioblastoma cell lines we observed that resistant cell lines lacked EGFR activation and expression. Furthermore, cell viability assays showed resistant cells were significantly less sensitive to the anti-EGFR agents when compared to parental cell lines. To further characterise the resistance mechanism in our cells microRNA prediction software identified miR-221 as a negative regulator of EGFR expression. miR-221 was up-regulated in our resistant cell lines, and this up-regulation led to a significant reduction in EGFR expression in both our cultured cell lines and a large cohort of glioblastoma patient tumor tissue.

SUBMITTER: Areeb Z

PROVIDER: S-EPMC7576591 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Areeb Zammam Z Stuart Sarah F SF West Alice J AJ Gomez Juliana J Nguyen Hong P T HPT Paradiso Lucia L Zulkifli Ahmad A Jones Jordan J Kaye Andrew H AH Morokoff Andrew P AP Luwor Rodney B RB

Scientific reports 20201020 1

Despite aggressive treatment with temozolomide and radiotherapy and extensive research into alternative therapies there has been little improvement in Glioblastoma patient survival. Median survival time remains between 12 and 15 months mainly due to treatment resistance and tumor recurrence. In this study, we aimed to explore the underlying mechanisms behind treatment resistance and the lack of success with anti-EGFR therapy in the clinic. After generating a number of treatment resistant Gliobla ...[more]

PMID: 33082482

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Project description:BACKGROUND:The tumor microenvironment (TME) plays a crucial role in virtually every aspect of tumorigenesis of glioblastoma multiforme (GBM). A dysfunctional TME promotes drug resistance, disease recurrence, and distant metastasis. Recent evidence indicates that exosomes released by stromal cells within the TME may promote oncogenic phenotypes via transferring signaling molecules such as cytokines, proteins, and microRNAs. RESULTS:In this study, clinical GBM samples were collected and analyzed. We found that GBM-associated macrophages (GAMs) secreted exosomes which were enriched with oncomiR-21. Coculture of GAMs (and GAM-derived exosomes) and GBM cell lines increased GBM cells' resistance against temozolomide (TMZ) by upregulating the prosurvival gene programmed cell death protein 4 (PDCD4) and stemness markers SRY (sex determining region y)-box 2 (Sox2), signal transducer and activator of transcription 3 (STAT3), Nestin, and miR-21-5p and increasing the M2 cytokines interleukin 6 (IL-6) and transforming growth factor beta 1(TGF-?1) secreted by GBM cells, promoting the M2 polarization of GAMs. Subsequently, pacritinib treatment suppressed GBM tumorigenesis and stemness; more importantly, pacritinib-treated GBM cells showed a markedly reduced ability to secret M2 cytokines and reduced miR-21-enriched exosomes secreted by GAMs. Pacritinib-mediated effects were accompanied by a reduction of oncomiR miR-21-5p, by which the tumor suppressor PDCD4 was targeted. We subsequently established patient-derived xenograft (PDX) models where mice bore patient GBM and GAMs. Treatment with pacritinib and the combination of pacritinib and TMZ appeared to significantly reduce the tumorigenesis of GBM/GAM PDX mice as well as overcome TMZ resistance and M2 polarization of GAMs. CONCLUSION:In summation, we showed the potential of pacritinib alone or in combination with TMZ to suppress GBM tumorigenesis via modulating STAT3/miR-21/PDCD4 signaling. Further investigations are warranted for adopting pacritinib for the treatment of TMZ-resistant GBM in clinical settings.

Project description:Background: Glioblastoma (GBM) prognosis remains extremely poor despite standard treatment that includes temozolomide (TMZ) chemotherapy. To discover new GBM drug targets and biomarkers, genes signatures associated with survival and TMZ resistance in GBM patients treated with TMZ were identified. Methods: GBM cases in The Cancer Genome Atlas who received TMZ (n = 221) were stratified into subgroups that differed by median overall survival (mOS) using network-based stratification to cluster patients whose somatic mutations affected genes in similar modules of a gene interaction network. Gene signatures formed from differentially mutated genes in the subgroup with the longest mOS were used to confirm their association with survival and TMZ resistance in independent datasets. Somatic mutations in these genes also were assessed for an association with OS in an independent group of 37 GBM cases. Results: Among the four subgroups identified, subgroup four (n = 71 subjects) exhibited the longest mOS at 18.3 months (95% confidence interval: 16.2, 34.1; p = 0.0324). Subsets of the 86 genes that were differentially mutated in this subgroup formed 20-gene and 8-gene signatures that predicted OS in two independent datasets (Spearman's rho of 0.64 and 0.58 between actual and predicted OS; p < 0.001). Patients with mutations in five of the 86 genes had longer OS in a small, independent sample of 37 GBM cases, but this association did not reach statistical significance (p = 0.07). Thirty-one of the 86 genes formed signatures that distinguished TMZ-resistant GBM samples from controls in three independent datasets (area under the curve ≥ 0.75). The prognostic and TMZ-resistance signatures had eight genes in common (ANG, BACH1, CDKN2C, HMGA1, IFI16, PADI4, SDF4, and TP53INP1). The latter three genes have not been associated with GBM previously. Conclusion: PADI4, SDF4, and TP53INP1 are novel therapy and biomarker candidates for GBM. Further investigation of their oncologic functions may provide new insight into GBM treatment resistance mechanisms.

Dataset Information

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

Publications

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

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