Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA

Nathanson, David; Gini, Beatrice; Mottahedeh, Jack; Visnyei, Koppany; Koga, Tomoyuki; Gomez, German G.; Eskin, Ascia; Hwang, Kiwook; Wang, Jun; Masui, Kenta; Paucar, Andres A.; Yang, Huijun; Ohashi, Masao; Zhu, Shaojun; Wykosky, Jill; Reed, Rachel; Nelson, Stanley F.; Cloughesy, Timothy F.; James, C. David; Rao, P. Nagesh; Kornblum, Harley I.; Heath, James R.; Cavenee, Webster K.; Furnari, Frank B.; Mischel, Paul S.

doi:10.1126/science.1241328

Cited by 520 publications

(586 citation statements)

References 33 publications

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“…GBM is an archetype example of a heterogeneous cancer (29) likely underlying the inability of conventional and targeted therapies to achieve long-term remission (30)(31)(32)(33). Singlecell RNA sequencing shows that GBM tumors consist of heterogeneous mixtures with individual cells corresponding to different GBM subtypes and this tumor heterogeneity influences clinical outcome (34).…”

Section: Discussionmentioning

confidence: 99%

Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity

Oizel

Chauvin

Oliver

et al. 2017

Clinical Cancer Research

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Purpose: Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer; however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof of concept for personalized metabolic targeting of GBM.Experimental Design: We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phenotyping assays, and mitochondrial respirometry.Results: We found that metabolic phenotyping clearly identifies 2 clusters, GLN High and GLN Low , mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLN High GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly proliferative GLN High cultures are CD133 neg and display a mesenchymal signature in contrast to CD133 pos GLN Low GBM cells. Conclusions: Our results show that metabolic phenotyping identified an essential metabolic pathway in a GBM cell subtype, and provide a proof of concept for theranostic metabolic targeting.

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Section: Discussionmentioning

confidence: 99%

Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity

Oizel

Chauvin

Oliver

et al. 2017

Clinical Cancer Research

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“…The constitutive activation of AKT and ERK in GBM cells increases the ability of survival, proliferation, migration and invasion (10). The radiosensitivity of GBM cells can be affected by AKT and ERK signaling pathways through promoting the activation of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) (28).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, ~40% of patients with GBM have an amplified EGFR gene which results in constitutive activation of AKT and ERK (10). AKT and ERK signaling pathways play vital roles in regulating many fundamental cellular processes and they are associated with resistance to treatment in GBM cells (11,12).…”

Section: Introductionmentioning

confidence: 99%

β-elemene enhances both radiosensitivity and chemosensitivity of glioblastoma cells through the inhibition of the ATM signaling pathway

et al. 2015

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Abstract. Glioblastoma multiforme (GBM), a tumor associated with poor prognosis, is known to be resistant to radiotherapy and alkylating agents such as temozolomide (TMZ). β-elemene, a monomer found in Chinese traditional herbs extracted from Curcuma wenyujin, is currently being used as an antitumor drug for different types of tumors including GBM. In the present study, we investigated the roles of β-elemene in the radiosensitivity and chemosensitivity of GBM cells. Human GBM cell lines U87-MG, T98G, U251, LN229 and rat C6 cells were treated with β-elemene combined with radiation or TMZ. We used MTT and colony forming assays to evaluate the proliferation and survival of the cells, and the comet assay to observe DNA damage. Expression of proteins was analyzed by immunoblotting. In the present study, we found that β-elemene inhibited the proliferation and survival of different GBM cell lines when combined with radiotherapy or TMZ via inhibition of DNA damage repair. Treatment of GBM cells with β-elemene decreased the phosphorylation of ataxia telangiectasia mutated (ATM), AKT and ERK following radiotherapy or chemotherapy. These results revealed that β-elemene could significantly increase the radiosensitivity and chemosensitivity of GBM. β-elemene may be used as a potential drug in combination with the radiotherapy and chemotherapy of GBM.

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“…The effect of EGFRvIII expression in promoting the tumorigenicity of GBM xenografts has been extensively documented. Originally attributed to an increase in proliferation along with a reduction in apoptosis due to an up-regulation of Bcl-XL, EGFRvIII has since been shown to stimulate GBM invasion, play key roles in mediating chemo-and radio-therapy resistance in GBM, and contribute to GBM heterogeneity (Nishikawa et al 1994, Nagane et al 1996, Nagane et al 1998, Nagane et al 2001, Lu et al 2009, Inda et al 2010, Nathanson et al 2014, Feng et al 2014.…”

Section: Alternative Splicing Of Egfrmentioning

confidence: 99%

Alternative RNA Splicing in the Pathogenesis of GBM

Thorne¹,

Cavenee²,

Furnari³

2015

MRAJ

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Abstract-Alternative splicing enables the generation of different proteins from a single gene, greatly increasing the use of genetic information. The resultant protein isoforms often have different biological properties effecting the phenotype of the cell in which it is expressed. Dysregulation of alternative splicing is a common occurrence in cancer and may lead to the formation of truncated or degraded proteins through the introduction of immature stop codons or nonsense mediated decay. Increasing evidence indicates that cancerassociated splicing variants play an important role in tumor initiation and progression. In this review, we summarize the evidence supporting the relevance of alternative splicing in glioblastoma multiforme (GBM). Specifically, we focus on the role of alternative splicing in GBM pathogenesis with an emphasis on the effect of aberrant alternative splicing of FGFR, GLI-1, and EGFR. The significance of exploiting alternatively spliced isoforms as potential biomarkers which may contribute to the development of diagnostic and prognostic methods, in addition to serving as molecular targets in GBM, will be discussed. Keywords-glioblastoma; alternative splicing Medical Research Archives 2015Issue 1 Copyright © 2015, Knowledge Enterprises Incorporated. All rights reserved. 2 INTRODUCTION Alternative splicing is a key regulator of gene expression and enables the generation of numerous transcripts from a single gene, thereby increasing the coding potential of the genome. During mRNA processing, approximately 90% of premRNA is removed as introns, with the remaining 10% joined together as exonic sequences (Tazi, Bakkour, and Stamm 2009). Thus the process has been considered a key driver in the evolution of phenotypic complexity. Splicing is the process by which introns are removed from a precursor mRNA (pre2mRNA) and exons are ligated to form a mature mRNA. Considered one of the most complicated RNA-protein complexes within the eukaryotic cell (Nilsen 2003), pre-mRNA splicing is catalyzed by the spliceosome, a large complex composed of five small nuclear ribonucleoprotein (RNP) subunits each composed of a single uridine rich small nuclear RNA (snRNA) in addition to as many as 150 proteins that assemble in an ordered stepwise manner on each intron to be spliced [reviewed in (Kim, Goren, and Ast 2008, Smith, Query, and Konarska 2008, Wahl, Will, and Luhrmann 2009. The spliceosome performs the two primary functions of splicing: recognition of the intron/exon boundaries and catalysis of the cut and paste reactions that remove introns and join exons. It is responsible for directing both constitutive and alternative splicing (Faustino and Cooper 2003).Definition of the exon/intron boundary is maintained through cis-regulatory RNA elements which serve as splicing enhancers or silencers, essentially determining the splice site. Splicing regulatory elements (SREs) fall into four different categories: exonic splicing enhancers (ESEs), intronic splicing enhancers (ISEs), exonic splicing silencers (ESSs), and in...

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Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA

Cited by 520 publications

References 33 publications

Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity

Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity

β-elemene enhances both radiosensitivity and chemosensitivity of glioblastoma cells through the inhibition of the ATM signaling pathway

Alternative RNA Splicing in the Pathogenesis of GBM

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