Oncogenic EGFR Signaling Networks in Glioma

Huang, Paul H.; Xu, Alexander M.; White, Forest M.

doi:10.1126/scisignal.287re6

Cited by 310 publications

(301 citation statements)

References 109 publications

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“…To further delineate the effect of loss of VPS4B function on EGFR signaling, we examined whether VPS4B knockdown affected the downstream signaling of the EGFR variant, EGFRvIII. Consistent with previous findings (19), NR6-EGFRvIII-expressing cells exhibited ligand-independent, constitutive Tyr phosphorylation of EGFRvIII in the absence of EGF (Fig. 4A).…”

Section: Resultssupporting

confidence: 80%

“…For example, EGFRvIII is the most common EGFR mutant, with an in-frame deletion of exons 2 to 7, and the lack of the corresponding amino acid residues 6 to 273 renders EGFRvIII constitutively tyrosine phosphorylated in a ligand-independent manner (reviewed in reference 19). Compared with EGFR, EGFRvIII has a low rate of endocytosis and thus escapes downregulation (18).…”

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confidence: 99%

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Identification of an AAA ATPase VPS4B-Dependent Pathway That Modulates Epidermal Growth Factor Receptor Abundance and Signaling during Hypoxia

Lin

Chen

et al. 2012

Molecular and Cellular Biology

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e VPS4B, an AAA ATPase (ATPase associated with various cellular activities), participates in vesicular trafficking and autophagosome maturation in mammalian cells. In solid tumors, hypoxia is a common feature and an indicator of poor treatment outcome. Our studies demonstrate that exogenous or endogenous (assessed with anchorage-independent three-dimensional multicellular spheroid culture) hypoxia induces VPS4B downregulation by the ubiquitin-proteasome system. Inhibition of VPS4B function by short hairpin VPS4B (sh-VPS4B) or expression of dominant negative VPS4B(E235Q) promotes anchorageindependent breast cancer cell growth and resistance to gefitinib, U0126, and genotoxicity. Biochemically, hyperactivation of epidermal growth factor receptor (EGFR), a receptor tyrosine kinase essential for cell proliferation and survival, accompanied by increased EGFR accumulation and altered intracellular compartmentalization, is observed in cells with compromised VPS4B. Furthermore, enhanced FOS/JUN induction and AP-1 promoter activation are noted in EGF-treated cells with VPS4B knockdown. However, VPS4B depletion does not affect EGFRvIII stability or its associated signaling. An inverse correlation between VPS4B expression and EGFR abundance is observed in breast tumors, and high-grade or recurrent breast carcinomas exhibit lower VPS4B expression. Together, our findings highlight a potentially critical role of VPS4B downregulation or chronichypoxia-induced VPS4B degradation in promoting tumor progression, unveiling a nongenomic mechanism for EGFR overproduction in human breast cancer.

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Section: Resultssupporting

confidence: 80%

mentioning

confidence: 99%

Identification of an AAA ATPase VPS4B-Dependent Pathway That Modulates Epidermal Growth Factor Receptor Abundance and Signaling during Hypoxia

Lin

Chen

et al. 2012

Molecular and Cellular Biology

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“…Multiple mechanisms can result in activation of the EGFR pathway during the initiation and development of GBM, including increased EGFR expression, enhanced autocrine signaling, and EGFR mutations (5). EGFR mutations commonly found in glioma typically involve the extracellular domains, such as the EGFRvIII mutant, as well as C-terminal deletion of the EGFR distal to the kinase domain (2).…”

Section: Discussionmentioning

confidence: 99%

“…Clinically, overexpression of EGFR has been correlated with poor prognosis in GBM patients (4), and the precise wiring of the EGFR network and the regulation of its signaling pathway in GBM have always been an area of active investigation. It is well known that multiple mechanisms are engaged in the activation of the EGFR pathway during tumor initiation and progression, including receptor amplification and activating receptor mutations (5). Intriguingly, EGFR mutations occurring in GBM often involve the deletions in the extracellular domain or cytoplasmic tails, such as the EGFRvIII mutant missing the extracellular ligand binding domain (5), whereas EGFR kinase domain mutations commonly found in nonsmall cell lung cancer (NSCLC) are rare in GBM, suggesting distinctive oncogenic EGFR networks in different tumor types.…”

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confidence: 99%

Mig-6 controls EGFR trafficking and suppresses gliomagenesis

Ying

Zheng

Scott

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

108

123

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Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer that is driven by aberrant signaling of growth factor receptors, particularly the epidermal growth factor receptor (EGFR). EGFR signaling is tightly regulated by receptor endocytosis and lysosome-mediated degradation, although the molecular mechanisms governing such regulation, particularly in the context of cancer, remain poorly delineated. Here, high-resolution genomic profiles of GBM identified a highly recurrent focal 1p36 deletion encompassing the putative tumor suppressor gene, Mig-6. We show that Mig-6 quells the malignant potential of GBM cells and dampens EGFR signaling by driving EGFR into late endosomes and lysosome-mediated degradation upon ligand stimulation. Mechanistically, this effect is mediated by the binding of Mig-6 to a SNARE protein STX8, a protein known to be required for late endosome trafficking. Thus, Mig-6 functions to ensure recruitment of internalized receptor to late endosomes and subsequently the lysosomal degradation compartment through its ability to specifically link EGFR and STX8 during ligand-stimulated EGFR trafficking. In GBM, the highly frequent loss of Mig-6 would therefore serve to sustain aberrant EGFR-mediated oncogenic signaling. Together, these data uncover a unique tumor suppression mechanism involving the regulation of receptor trafficking.

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“…Epidermal growth factor receptor (EGFR), also called ErbB1/ HER1, plays an important role in tumor development by stimulating cell proliferation and cell resistance to apoptosis and autophagy (2). It also participates in drug and radiotherapy resistance via stimulation of different pathways such as Ras-Raf-ERK and PI3K-AKT-mTOR (3).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma

Zahonero

Aguilera

Ramírez-Castillejo

et al. 2015

Molecular Cancer Therapeutics

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Glioblastomas (GBM) are devastating tumors in which there has been little clinical improvement in the last decades. New molecularly directed therapies are under development. EGFR is one of the most promising targets, as this receptor is mutated and/or overexpressed in nearly half of the GBMs. However, the results obtained with first-generation tyrosine-kinase inhibitors have been disappointing with no clear predictive markers of tumor response. Here, we have tested the antitumoral efficacy of a second-generation inhibitor, dacomitinib (PF299804, Pfizer), that binds in an irreversible way to the receptor. Our results confirm that dacomitinib has an effect on cell viability, self-renewal, and proliferation in EGFR-amplified AE EGFRvIII GBM cells. Moreover, systemic administration of dacomitinib strongly impaired the in vivo tumor growth rate of these EGFR-amplified cell lines, with a decrease in the expression of stem cell-related markers. However, continuous administration of the compound was required to maintain the antitumor effect. The data presented here confirm that dacomitinib clearly affects receptor signaling in vivo and that its strong antitumoral effect is independent of the presence of mutant receptor isoforms although it could be affected by the PTEN status (as it is less effective in a PTEN-deleted GBM line). Dacomitinib is being tested in second line for EGFR-amplified GBMs. We hope that our results could help to select retrospectively molecular determinants of this response and to implement future trials with dacomitinib (alone or in combination with other inhibitors) in newly diagnosed GBMs. Mol Cancer Ther; 14(7); 1548-58. Ó2015 AACR.

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Oncogenic EGFR Signaling Networks in Glioma

Cited by 310 publications

References 109 publications

Identification of an AAA ATPase VPS4B-Dependent Pathway That Modulates Epidermal Growth Factor Receptor Abundance and Signaling during Hypoxia

Identification of an AAA ATPase VPS4B-Dependent Pathway That Modulates Epidermal Growth Factor Receptor Abundance and Signaling during Hypoxia

Mig-6 controls EGFR trafficking and suppresses gliomagenesis

Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma

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