Epidermal growth factor receptor and notch signaling in non‐small‐cell lung cancer

Pancewicz-Wojtkiewicz, Joanna

doi:10.1002/cam4.944

Cited by 43 publications

(21 citation statements)

References 43 publications

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“…Indeed, aberrant Notch signaling has been observed in a variety of cancers, with its signaling or expression either being pro- or anti- tumorigenic, highly dependent on the tissue and cellular context[253–255]. Interestingly, oncogenic EGFR signaling and Notch signaling have been considered mutual or correlative[256], which could potentially be related to a common role for DUOX1/DUOXA1 on these processes. Beyond its role as a maturation factor for DUOX1, or in regulating the Notch pathway, DUOXA1 may also have other independent functional roles.…”

Section: Duox and Their Maturation Factors: Partners Or Enemies?mentioning

confidence: 99%

Paradoxical roles of dual oxidases in cancer biology

Little

Sulovari

Danyal

et al. 2017

Free Radical Biology and Medicine

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Dysregulated oxidative metabolism is a well-recognized aspect of cancer biology, and many therapeutic strategies are based on targeting cancers by altering cellular redox pathways. The NADPH oxidases (NOXes) present an important enzymatic source of biological oxidants, and the expression and activation of several NOX isoforms are frequently dysregulated in many cancers. Cell-based studies have demonstrated a role for several NOX isozymes in controlling cell proliferation and/or cell migration, further supporting a potential contributing role for NOX in promoting cancer. While various NOX isoforms are often upregulated in cancers, paradoxical recent findings indicate that dual oxidases (DUOXes), normally prominently expressed in epithelial lineages, are frequently suppressed in epithelial-derived cancers by epigenetic mechanisms, although the functional relevance of such DUOX silencing has remained unclear. This review will briefly summarize our current understanding regarding the importance of reactive oxygen species (ROS) and NOXes in cancer biology, and focus on recent observations indicating the unique and seemingly opposing roles of DUOX enzymes in cancer biology. We will discuss current knowledge regarding the functional properties of DUOX, and recent studies highlighting mechanistic consequences of DUOX1 loss in lung cancer, and its consequences for tumor invasiveness and current anticancer therapy. Finally, we will also discuss potentially unique roles for the DUOX maturation factors. Overall, a better understanding of mechanisms that regulate DUOX and the functional consequences of DUOX silencing in cancer may offer valuable new diagnostic insights and novel therapeutic opportunities.

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Section: Duox and Their Maturation Factors: Partners Or Enemies?mentioning

confidence: 99%

Paradoxical roles of dual oxidases in cancer biology

Little

Sulovari

Danyal

et al. 2017

Free Radical Biology and Medicine

View full text Add to dashboard Cite

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“…EGF is involved in endothelial dysfunction, neointimal hyperplasia, cardiac hypertrophy and remodeling [88] and, as shown by us, reduction in circulating levels of EGF could be involved in the ticagrelor-mediated improvement of endothelial function in stable CAD/COPD patients [2]. The cross-talk between EGF and Notch signaling is well characterized: EGF and Notch pathways can cooperate in either synergistic or antagonistic fashion in malignancies [89] and the EGF, via EGFR, acts as a negative regulator of HES1 expression in keratinocytes [90]. On the contrary, little is known on the cross-talk between EGF/SIRT1.…”

Section: Discussionmentioning

confidence: 85%

Ticagrelor Increases SIRT1 and HES1 mRNA Levels in Peripheral Blood Cells from Patients with Stable Coronary Artery Disease and Chronic Obstructive Pulmonary Disease

Aquila

Sega

Marracino

et al. 2020

IJMS

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Ticagrelor is a powerful P2Y12 inhibitor with pleiotropic effects in the cardiovascular system. Consistently, we have reported that in patients with stable coronary artery disease (CAD) and concomitant chronic obstructive pulmonary disease (COPD) who underwent percutaneous coronary intervention (PCI), 1-month treatment with ticagrelor was superior in improving biological markers of endothelial function, compared with clopidogrel. The objective of this study was to investigate the mechanisms underlying these beneficial effects of ticagrelor by conducting molecular analyses of RNA isolated from peripheral blood cells of these patients. We determined mRNAs levels of markers of inflammation and oxidative stress, such as RORγt (T helper 17 cells marker), FoxP3 (regulatory T cells marker), NLRP3, ICAM1, SIRT1, Notch ligands JAG1 and DLL4, and HES1, a Notch target gene. We found that 1-month treatment with ticagrelor, but not clopidogrel, led to increased levels of SIRT1 and HES1 mRNAs. In patients treated with ticagrelor or clopidogrel, we observed a negative correlation among changes in both SIRT1 and HES1 mRNA and serum levels of Epidermal Growth Factor (EGF), a marker of endothelial dysfunction found to be reduced by ticagrelor treatment in our previous study. In conclusion, we report that in stable CAD/COPD patients ticagrelor positively regulates HES1 and SIRT1, two genes playing a protective role in the context of inflammation and oxidative stress. Our observations confirm and expand previous studies showing that the beneficial effects of ticagrelor in stable CAD/COPD patients may be, at least in part, mediated by its capacity to reduce systemic inflammation and oxidative stress.

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“…EGFR and NOTCH pathways are both important in cell proliferation, differentiation, and apoptosis, and have a fundamental role during the development of multicellular organisms. The interaction of these two pathways has been reported in diverse biological processes with significant phenotypic outcomes, in particular, drug resistance [ 79 , 80 , 81 , 82 ]. Our finding that the genes of the NOTCH pathways were mutated to a substantial degree in the context of activated mutant EGFRs further confirm the notion that a combinational treatment consisting of EGFR and NOTCH inhibition could be a promising therapeutic strategy for NSCLC patients.…”

Section: Resultsmentioning

confidence: 99%

Genomic Profiling on an Unselected Solid Tumor Population Reveals a Highly Mutated Wnt/β-Catenin Pathway Associated with Oncogenic EGFR Mutations

Jiang¹,

Protopopov

Sun³

et al. 2018

JPM

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Oncogenic epidermal growth factor receptors (EGFRs) can recruit key effectors in diverse cellular processes to propagate oncogenic signals. Targeted and combinational therapeutic strategies have been successfully applied for treating EGFR-driven cancers. However, a main challenge in EGFR therapies is drug resistance due to mutations, oncogenic shift, alternative signaling, and other potential mechanisms. To further understand the genetic alterations associated with oncogenic EGFRs and to provide further insight into optimal and personalized therapeutic strategies, we applied a proprietary comprehensive next-generation sequencing (NGS)-based assay of 435 genes to systematically study the genomic profiles of 1565 unselected solid cancer patient samples. We found that activating EGFR mutations were predominantly detected in lung cancer, particularly in non-small cell lung cancer (NSCLC). The mutational landscape of EGFR-driven tumors covered most key signaling pathways and biological processes. Strikingly, the Wnt/β-catenin pathway was highly mutated (48 variants detected in 46% of the EGFR-driven tumors), and its variant number topped that in the TP53/apoptosis and PI3K-AKT-mTOR pathways. Furthermore, an analysis of mutation distribution revealed a differential association pattern of gene mutations between EGFR exon 19del and EGFR L858R. Our results confirm the aggressive nature of the oncogenic EGFR-driven tumors and reassure that a combinational strategy should have advantages over an EGFR-targeted monotherapy and holds great promise for overcoming drug resistance.

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Epidermal growth factor receptor and notch signaling in non‐small‐cell lung cancer

Cited by 43 publications

References 43 publications

Paradoxical roles of dual oxidases in cancer biology

Paradoxical roles of dual oxidases in cancer biology

Ticagrelor Increases SIRT1 and HES1 mRNA Levels in Peripheral Blood Cells from Patients with Stable Coronary Artery Disease and Chronic Obstructive Pulmonary Disease

Genomic Profiling on an Unselected Solid Tumor Population Reveals a Highly Mutated Wnt/β-Catenin Pathway Associated with Oncogenic EGFR Mutations

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