EGFR as a Target for Glioblastoma Treatment: An Unfulfilled Promise

Westphal, Manfred; Maire, Cécile L.; Lamszus, Katrin

doi:10.1007/s40263-017-0456-6

Cited by 182 publications

(137 citation statements)

References 134 publications

(134 reference statements)

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“…EGFR and its structural variants have been targeted extensively in GBM, but with limited success. We suggest further study of the mechanisms by which EEA1 contributes to the TMZ resistant phenotype could provide a new way to target EGFR by modifying its subcellular localization rather than activation 26 . In addition to an accumulation of early endosomes, we observed vesicles expelled into the media of the resistant cell lines.…”

Section: Discussionmentioning

confidence: 97%

Alterations in Cell Motility, Proliferation, and Metabolism in Novel Models of Acquired Temozolomide Resistant Glioblastoma

Tiek

Rone

Graham

et al. 2017

Preprint

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Glioblastoma (GBM) is an aggressive and incurable tumor of the brain with limited treatment options. Current first-line standard of care is the DNA alkylating agent temozolomide (TMZ), but this treatment strategy adds only ~4 months to median survival due to the rapid development of resistance. While some mechanisms of TMZ resistance have been identified, they are not fully understood. There are few effective strategies to manage therapy resistant GBM, and we lack diverse preclinical models of acquired TMZ resistance in which to test therapeutic strategies on TMZ resistant GBM. In this study, we create and characterize two new GBM cell lines resistant to TMZ, based on the 8MGBA and 42MGBA cell lines. Analysis of the TMZ resistant (TMZres) variants in conjunction with their parental, sensitive cell lines shows that acquisition of TMZ resistance is accompanied by broad phenotypic changes, including increased proliferation, migration, chromosomal aberrations and secretion of cytosolic lipids. Importantly, each TMZ resistant model captures a different facet of the "go" (8MGBA-TMZres) or "grow" (42MGBA-TMZres) hypothesis of GBM behavior. These model systems will be important additions to the available tools for investigators seeking to define molecular mechanisms of acquired TMZ resistance.. CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a

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Section: Discussionmentioning

confidence: 97%

Alterations in Cell Motility, Proliferation, and Metabolism in Novel Models of Acquired Temozolomide Resistant Glioblastoma

Tiek

Rone

Graham

et al. 2017

Preprint

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“…The contextual selection of mutations averting the kinase catalytic domain in glioma suggests alternate adaptation of the EGFR signaling pathway. For cancer management, although tyrosine kinase inhibitors blocking EGFR are common in the therapeutic armamentarium of lung cancer (46,47), these agents have not been successful in treating glioma even with improved drug delivery techniques to penetrate the blood-brain barrier (48)(49)(50). Our findings offer a new direction to investigating and enhancing current treatment regimen.…”

Section: Application To Tcga Datamentioning

confidence: 93%

Contextual Classifications of Cancer Driver Genes

Chandrashekar

Ahmadinejad

Wang

et al. 2019

Preprint

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Functions of cancer driver genes depend on cellular contexts that vary substantially across tissues and organs. Distinguishing oncogenes (OGs) and tumor suppressor genes (TSGs) for each cancer type is critical to identifying clinically actionable targets. However, current resources for context-aware classifications of cancer drivers are limited. In this study, we show that the direction and magnitude of somatic selection of missense and truncating mutations of a gene are suggestive of its contextual activities. By integrating these features with ratiometric and conservation measures, we developed a computational method to categorize OGs and TSGs using exome sequencing data. This new method, named genes under selection in tumors (GUST) shows an overall accuracy of 0.94 when tested on manually curated benchmarks. Application of GUST to 10,172 tumor exomes of 33 cancer types identified 98 OGs and 179 TSGs, >70% of which promote tumorigenesis in only one cancer type. In broad-spectrum drivers shared across multiple cancer types, we found heterogeneous mutational hotspots modifying distinct functional domains, implicating the synchrony of convergent and divergent disease mechanisms. We further discovered two novel OGs and 28 novel TSGs with high confidence.The GUST program is available at https://github.com/liliulab/gust. A database with pre-computed classifications is available at https://liliulab.shinyapps.io/gust

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“…Treatment with EGFR‐TKIs can significantly improve overall and disease‐free survival in NSCLC patients with effective EGFR gene mutations. Therefore, evaluation of EGFR mutation status is recommended in patients with NSCLC before administering target drugs . However, it is difficult to obtain adequate cancer tissue for EGFR mutation detection in some NSCLC patients.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, evaluation of EGFR mutation status is recommended in patients with NSCLC before administering target drugs. [9][10][11] However, it is difficult to obtain adequate cancer tissue for EGFR mutation detection in some NSCLC patients. Thus, predicting effective EGFR mutation by clinical and demographic characteristics and imaging features is important.…”

Section: Introductionmentioning

confidence: 99%

Relationship between EGFR mutation and computed tomography characteristics of the lung in patients with lung adenocarcinoma

2018

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BackgroundThe aim of this study was to investigate the relationship between EGFR mutation and computed tomography (CT) features in patients with adenocarcinoma of the lung.MethodsOne hundred and ninety two lung adenocarcinoma patients who underwent surgery were retrospectively included in this study. Examination of EGFR gene mutation was performed on all resected tumor samples. The 192 recruited lung adenocarcinoma patients were divided into groups according to EGFR mutation status: patients with mutations in exons 18–21 (effective mutated, n = 61) and non‐mutated (n = 131). The clinical characteristics and lung CT imaging features of the two groups were recorded and compared. Univariate and logistic regression analysis were performed to identify the independent risk factors relevant to effective EGFR gene mutation.ResultsThe independent risk factors relevant to effective EGFR mutation were evaluated by logistic regression test. The results indicated that female gender (odds ratio [OR] 3.23), lung CT features of lymphangitis carcinomatosa (OR 2.66), semi‐solid lesion density (OR 3.56), and spicule sign (OR 1.61) were independent risk factors relevant to EGFR mutation.ConclusionFemale patients with lung CT features of lymphangitis carcinomatosa, semi‐solid lesion density, and spicule sign are more prone to harbor EGFR gene mutations and are more likely to benefit from targeted therapy.

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EGFR as a Target for Glioblastoma Treatment: An Unfulfilled Promise

Cited by 182 publications

References 134 publications

Alterations in Cell Motility, Proliferation, and Metabolism in Novel Models of Acquired Temozolomide Resistant Glioblastoma

Alterations in Cell Motility, Proliferation, and Metabolism in Novel Models of Acquired Temozolomide Resistant Glioblastoma

Contextual Classifications of Cancer Driver Genes

Relationship between EGFR mutation and computed tomography characteristics of the lung in patients with lung adenocarcinoma

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