Dataset Information

Non-Canonical Activation of the Epidermal Growth Factor Receptor by Carbon Nanoparticles.

ABSTRACT: The epidermal growth factor receptor (EGFR) is an abundant membrane protein, which is essential for regulating many cellular processes including cell proliferation. In our earlier studies, we observed an activation of the EGFR and subsequent signaling events after the exposure of epithelial cells to carbon nanoparticles. In the current study, we describe molecular mechanisms that allow for discriminating carbon nanoparticle-specific from ligand-dependent receptor activation. Caveolin-1 is a key player that co-localizes with the EGFR upon receptor activation by carbon nanoparticles. This specific process mediated by nanoparticle-induced reactive oxygen species and the accumulation of ceramides in the plasma membrane is not triggered when cells are exposed to non-nano carbon particles or the physiological ligand EGF. The role of caveolae formation was demonstrated by the induction of higher order structures of caveolin-1 and by the inhibition of caveolae formation. Using an in vivo model with genetically modified mice lacking caveolin-1, it was possible to demonstrate that carbon nanoparticles in vivo trigger EGFR downstream signaling cascades via caveolin-1. The identified molecular mechanisms are, therefore, of toxicological relevance for inhaled nanoparticles. However, nanoparticles that are intentionally applied to humans might cause side effects depending on this phenomenon.

SUBMITTER: Stockmann D

PROVIDER: S-EPMC5923597 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Non-Canonical Activation of the Epidermal Growth Factor Receptor by Carbon Nanoparticles.

Stöckmann Daniel D Spannbrucker Tim T Ale-Agha Niloofar N Jakobs Philipp P Goy Christine C Dyballa-Rukes Nadine N Hornstein Tamara T Kümper Alexander A Kraegeloh Annette A Haendeler Judith J Unfried Klaus K

Nanomaterials (Basel, Switzerland) 20180423 4

The epidermal growth factor receptor (EGFR) is an abundant membrane protein, which is essential for regulating many cellular processes including cell proliferation. In our earlier studies, we observed an activation of the EGFR and subsequent signaling events after the exposure of epithelial cells to carbon nanoparticles. In the current study, we describe molecular mechanisms that allow for discriminating carbon nanoparticle-specific from ligand-dependent receptor activation. Caveolin-1 is a key ...[more]

PMID: 29690640

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Project description:PurposeSubset analyses from phase III evaluation of epidermal growth factor receptor inhibition (EGFRi) suggest improved outcomes in patients with EGFR-amplified gastroesophageal adenocarcinoma (GEA), but large-scale analyses are lacking. This multi-institutional analysis sought to determine the role of EGFRi in the largest cohort of patients with EGFR-amplified GEA to date.Patients and methodsA total of 60 patients from 15 tertiary cancer centers in six countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments-approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing, plasma circulating tumor DNA next-generation sequencing, and/or fluorescence in situ hybridization performed by a Clinical Laboratory Improvement Amendments approved laboratory. Treatment patterns and outcomes analysis was also performed using a deidentified clinicogenomic database (CGDB).ResultsSixty patients with EGFR-amplified GEA received EGFRi, including 31 of 60 patients (52%) with concurrent chemotherapy. Across treatment lines, patients achieved a 43% objective response rate with a median progression-free survival of 4.6 months (95% CI, 3.5 to 6.4). Patients receiving EGFRi in first-, second-, and third-line therapy achieved a median overall survival of 20.6 months (95% CI, 13.5 to not reached [NR]), 9 months (95% CI, 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95% CI, 8.7 to 14.2) median overall survival from first-line initiation of non-EGFRi therapy in patients with EGFR-amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011-December 2020) suggests that only 5% of patients with EGFR-amplified GEA received EGFRi.ConclusionPatients with EGFR-amplified GEA derive significant benefit from EGFRi. Further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

Dataset Information

Non-Canonical Activation of the Epidermal Growth Factor Receptor by Carbon Nanoparticles.

Publications

Non-Canonical Activation of the Epidermal Growth Factor Receptor by Carbon Nanoparticles.

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