The TICking clock of EGFR therapy resistance in glioblastoma: Target Independence or target Compensation

Saleem, Hamza; Abdul, U. Kulsoom; Küçükosmanoğlu, Aslı; Houweling, Megan; Cornelissen, Ferry; Heiland, Dieter Henrik; Hegi, Monika E.; Kouwenhoven, Mathilde C.M.; Bailey, David; Würdinger, Tom; Westerman, Bart A.

doi:10.1016/j.drup.2019.04.002

Cited by 36 publications

(22 citation statements)

References 65 publications

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“…There is evidence that targeted therapy towards mutations responsible for cancer growth and progression is effective in different tumor types. For GBM, the responses to EGFR-pathway inhibitors were not as expected, and they are mainly explained by drug resistance [ 141 ]. Two major mechanisms could explain the EGFR therapy resistance.…”

Section: Facing a Real Challenge—drug Resistancementioning

confidence: 99%

Updated Insights on EGFR Signaling Pathways in Glioma

Opriţa

Baloi

Staicu

et al. 2021

IJMS

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Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood–brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.

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Section: Facing a Real Challenge—drug Resistancementioning

confidence: 99%

Updated Insights on EGFR Signaling Pathways in Glioma

Opriţa

Baloi

Staicu

et al. 2021

IJMS

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“…One unique pathway involved, EGFR signaling, has been implicated in glucose homeostasis by regulating beta-cell proliferation in response to increased metabolic demand [ 53 ]. Notably, EGFR signaling is associated with IGF-IR expression and IGF-I secretion in cancer cells [ 54 , 55 ], contributing to cancer cell growth and poor survival; thus, dual targeting at EGFR and the IGF/IR axis has been suggested to be a promising therapeutic strategy for overcoming drug-acquired resistance in several cancer types, such as lung adenocarcinoma, head and neck squamous cell and colorectal carcinomas, and glioblastoma [ 55 , 56 , 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Multi-Omics Data Analysis Uncovers Molecular Networks and Gene Regulators for Metabolic Biomarkers

Jung

2021

Biomolecules

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The insulin-like growth factors (IGFs)/insulin resistance (IR) axis is the major metabolic hormonal pathway mediating the biologic mechanism of several complex human diseases, including type 2 diabetes (T2DM) and cancers. The genomewide association study (GWAS)-based approach has neither fully characterized the phenotype variation nor provided a comprehensive understanding of the regulatory biologic mechanisms. We applied systematic genomics to integrate our previous GWAS data for IGF-I and IR with multi-omics datasets, e.g., whole-blood expression quantitative loci, molecular pathways, and gene network, to capture the full range of genetic functionalities associated with IGF-I/IR and key drivers (KDs) in gene-regulatory networks. We identified both shared (e.g., T2DM, lipid metabolism, and estimated glomerular filtration signaling) and IR-specific (e.g., mechanistic target of rapamycin, phosphoinositide 3-kinases, and erb-b2 receptor tyrosine kinase 4 signaling) molecular biologic processes of IGF-I/IR axis regulation. Next, by using tissue-specific gene–gene interaction networks, we identified both well-established (e.g., IRS1 and IGF1R) and novel (e.g., AKT1, HRAS, and JAK1) KDs in the IGF-I/IR-associated subnetworks. Our results, if validated in additional genomic studies, may provide robust, comprehensive insights into the mechanisms of IGF-I/IR regulation and highlight potential novel genetic targets as preventive and therapeutic strategies for the associated diseases, e.g., T2DM and cancers.

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“…Current standard treatment for glioma patients includes maximum safe surgical resection, simultaneous radiotherapy and temozolomide, and then adjuvant temozolomide. Glioma is still an incurable disease, the average OS after standard treatment is 12-15 months, and relapse is inevitable [39]. Therefore, it is extremely important to explore new methods to improve the prognosis of glioma patients and improve the quality of life of patients.…”

Section: Discussionmentioning

confidence: 99%

The Expression and Prognostic Values of Epidermal Growth Factor Receptor Family in Glioma

Huo

et al. 2021

Preprint

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Background: Epidermal growth factor receptor (EGFR) family belongs to the transmembrane protein receptor of tyrosine kinase I subfamily, including 4 members, they are EGFR/ERBB1, ERBB2, ERBB3, ERBB4. The EGFR family is closely related to the occurrence and development of a variety of cancers.Material/Methods: In this research, we used multiple online bioinformatics websites including ONCOMINE, TCGA, CGGA, TIMER, cBioPortal, GeneMANIA and DAVID to study the expression profiles, prognostic values and immune infiltration correlations of EGFR family in glioma.Results: We found that EGFR and ERBB2 mRNA expression levels were the higher in glioblastoma (GBM, WHO IV) than other grades (WHO grade II&III), While ERBB3 and ERBB4 mRNA expression levels were opposite. EGFR and ERBB2 were notably downregulated in IDH mutant gliomas, while ERBB3 and ERBB4 were the opposite. Besides, ERBB2 and ERBB4 in glioma patients were associated with poor prognosis. In addition, correlation analysis between EGFR family expression and immune infiltrating levels in glioma showed that EGFR family expression and immune infiltrating levels were significantly correlated. PPI network of EGFR family in glioma and enrichment analysis showed that EGFR family and their interactors mainly participated in regulation of cell motility involved integrin receptors and Rho family GTPases.Conclusions: In summary, this study indicates that EGFR family may become potential targets and new prognostic markers for glioma.

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The TICking clock of EGFR therapy resistance in glioblastoma: Target Independence or target Compensation

Cited by 36 publications

References 65 publications

Updated Insights on EGFR Signaling Pathways in Glioma

Updated Insights on EGFR Signaling Pathways in Glioma

Multi-Omics Data Analysis Uncovers Molecular Networks and Gene Regulators for Metabolic Biomarkers

The Expression and Prognostic Values of Epidermal Growth Factor Receptor Family in Glioma

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