scholarly journals LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance

Oncogene ◽  
2021 ◽  
Author(s):  
Ola Billing ◽  
Ylva Holmgren ◽  
Daniel Nosek ◽  
Håkan Hedman ◽  
Oskar Hemmingsson
Keyword(s):  
Growth Factor Receptor ◽  
Braf Inhibitor ◽  
Treatment Resistance ◽  
Negative Regulator ◽  
C Elegans ◽  
Rtk Signaling ◽  
Egfr Expression ◽  
Inhibitor Resistance ◽  
Leucine Rich Repeats

AbstractLeucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-negative regulator of receptor tyrosine kinase (RTK) signaling and a tumor suppressor in several cancers, but its involvement in melanoma is largely unexplored. Here, we aim to determine the role of LRIG1 in melanoma tumorigenesis, RTK signaling, and BRAF inhibitor resistance. We find that LRIG1 is downregulated during early tumorigenesis and that LRIG1 affects activation of the epidermal growth factor receptor (EGFR) in melanoma cells. LRIG1-dependent regulation of EGFR signaling is evolutionary conserved to the roundworm C. elegans, where negative regulation of the EGFR-Ras-Raf pathway by sma-10/LRIG completely depends on presence of the receptor let-23/EGFR. In a cohort of metastatic melanoma patients, we observe an association between LRIG1 and survival in the triple wild-type subtype and in tumors with high EGFR expression. During in vitro development of BRAF inhibitor resistance, LRIG1 expression decreases; and mimics LRIG1 knockout cells for increased EGFR expression. Treating resistant cells with recombinant LRIG1 suppresses AKT activation and proliferation. Together, our results show that sma-10/LRIG is a conserved regulator of RTK signaling, add to our understanding of LRIG1 in melanoma and identifies recombinant LRIG1 as a potential therapeutic against BRAF inhibitor-resistant melanoma.

The epidermal growth factor receptor is a relevant host factor in the early stages of Zika virus life cycle in vitro

2021 ◽  
Author(s):  
Catarina Sabino ◽  
Daniela Bender ◽  
Marie-Luise Herrlein ◽  
Eberhard Hildt
Keyword(s):  
Life Cycle ◽  
Zika Virus ◽  
A549 Cells ◽  
Growth Factor Receptor ◽  
Viral Life Cycle ◽  
Infection Process ◽  
Zikv Infection ◽  
Early Stages ◽  
Egfr Expression

Zika virus (ZIKV) is a flavivirus well-known for the epidemic in the Americas in 2015-2016, where microcephaly in newborns and other neurological complications were connected to ZIKV infection. Many aspects of the viral life cycle, including binding and entry into the host cell, are still enigmatic. Based on the observation that CHO cells lack the expression of EGFR and are not permissive for various ZIKV strains, the relevance of EGFR for the viral life cycle was analyzed. Infection of A549 cells by ZIKV leads to a rapid internalization of EGFR that colocalizes with the endosomal marker EEA1. Moreover, the infection by different ZIKV strains is associated with an activation of EGFR and subsequent activation of the MAPK/ERK signaling cascade. However, treatment of the cells with MβCD, which on the one hand leads to an activation of EGFR but on the other hand prevents EGFR internalization, impairs ZIKV infection. Specific inhibition of EGFR or of the RAS-RAF-MEK-ERK signal transduction cascade hinders ZIKV infection by inhibition of ZIKV entry. In accordance to this, knockout of EGFR expression impedes ZIKV entry. In case of an already established infection, inhibition of EGFR or of downstream signaling does not affect viral replication. Taken together, these data demonstrate the relevance of EGFR in the early stages of ZIKV infection and identify EGFR as a target for antiviral strategies. Importance These data deepen the knowledge about the ZIKV infection process and demonstrate the relevance of EGFR for ZIKV entry. In light of the fact that a variety of specific and efficient inhibitors of EGFR and of EGFR-dependent signaling were developed and licensed, repurposing of these substances could be a helpful tool to prevent the spreading of ZIKV infection in an epidemic outbreak.

scholarly journals Patient-Derived Head and Neck Cancer Organoids Recapitulate EGFR Expression Levels of Respective Tissues and Are Responsive to EGFR-Targeted Photodynamic Therapy

2019 ◽  
Vol 8 (11) ◽  
pp. 1880 ◽  
Author(s):  
Else Driehuis ◽  
Sacha Spelier ◽  
Irati Beltrán Hernández ◽  
Remco de Bree ◽  
Stefan M. Willems ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Head And Neck ◽  
Three Dimensional ◽  
Growth Factor Receptor ◽  
Therapeutic Interventions ◽  
Expression Levels ◽  
Tumor Patient ◽  
Normal Tissues ◽  
Egfr Expression

Patients diagnosed with head and neck squamous cell carcinoma (HNSCC) are currently treated with surgery and/or radio- and chemotherapy. Despite these therapeutic interventions, 40% of patients relapse, urging the need for more effective therapies. In photodynamic therapy (PDT), a light-activated photosensitizer produces reactive oxygen species that ultimately lead to cell death. Targeted PDT, using a photosensitizer conjugated to tumor-targeting molecules, has been explored as a more selective cancer therapy. Organoids are self-organizing three-dimensional structures that can be grown from both normal and tumor patient-material and have recently shown translational potential. Here, we explore the potential of a recently described HNSCC–organoid model to evaluate Epidermal Growth Factor Receptor (EGFR)-targeted PDT, through either antibody- or nanobody-photosensitizer conjugates. We find that EGFR expression levels differ between organoids derived from different donors, and recapitulate EGFR expression levels of patient material. EGFR expression levels were found to correlate with the response to EGFR-targeted PDT. Importantly, organoids grown from surrounding normal tissues showed lower EGFR expression levels than their tumor counterparts, and were not affected by the treatment. In general, nanobody-targeted PDT was more effective than antibody-targeted PDT. Taken together, patient-derived HNSCC organoids are a useful 3D model for testing in vitro targeted PDT.

scholarly journals Synthesis, Microtubule-Binding Affinity, and Antiproliferative Activity of New Epothilone Analogs and of an EGFR-Targeted Epothilone-Peptide Conjugate

2019 ◽  
Vol 20 (5) ◽  
pp. 1113 ◽  
Author(s):  
Fabienne Gaugaz ◽  
Andrea Chicca ◽  
Mariano Redondo-Horcajo ◽  
Isabel Barasoain ◽  
J. Díaz ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Antiproliferative Activity ◽  
Growth Factor Receptor ◽  
Side Chain ◽  
Cancer Cell Growth ◽  
Microtubule Binding ◽  
Egfr Expression ◽  
Epidermal Growth ◽  
Viable Approach

A new simplified, epoxide-free epothilone analog was prepared incorporating an N-(2-hydroxyethyl)-benzimidazole side chain, which binds to microtubules with high affinity and inhibits cancer cell growth in vitro with nM potency. Building on this scaffold, a disulfide-linked conjugate with the purported EGFR-binding (EGFR, epidermal growth factor receptor) peptide GE11 was then prepared. The conjugate retained significant microtubule-binding affinity, in spite of the size of the peptide attached to the benzimidazole side chain. The antiproliferative activity of the conjugate was significantly lower than for the parent scaffold and, surprisingly, was independent of the EGFR expression status of cells. Our data indicate that the disulfide-based conjugation with the GE11 peptide is not a viable approach for effective tumor-targeting of highly potent epothilones and probably not for other cytotoxics.

scholarly journals CD34 is a target for covalent EGFR inhibitors to eliminate stem/progenitor cells in acute and chronic myeloid leukemia

2021 ◽  
Author(s):  
Ying Lu ◽  
Li Xia ◽  
Li-Xue Yang ◽  
Hong-Chen Liu ◽  
Yue Jiang ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Growth Factor Receptor ◽  
Egfr Inhibitors ◽  
Stem Cell Marker ◽  
Cd34 Antigen ◽  
Egfr Expression ◽  
Stat3 Phosphorylation

Abstract The effect of epidermal growth factor receptor (EGFR) inhibitors on acute myeloid leukemia (AML) was discovered over one decade ago. However, clinical trials of EGFR inhibitors in AML have yielded controversial outcomes. Leukemia cells lack EGFR expression, and the mechanism by which EGFR inhibitors affect leukemia cell growth is unknown, obscuring the precise subset of AML patients that might be targeted by these compounds. Since myeloid leukemia arises from malignant stem/progenitors, here we evaluated the effect of EGFR inhibitors on primary leukemia stem/progenitors that expressed the stem cell marker CD34 which were sorted from leukemia patients. EGFR inhibitors induced significant apoptosis of primary CD34+ but not CD34− cells derived from AML and chronic myeloid leukemia (CML) patients both in vitro and in patient-derived xenotransplantation model. Using two EGFR inhibitors osimertinib and afatinib, we demonstrated binding and covalent adducts of the inhibitors with the cysteine(C) 199 residue of the CD34 protein, which downregulated phosphorylation of tyrosine 329(Y329) of CD34, leading to the dissociation of CD34 from tyrosine kinase Src and thereafter the inhibition of STAT3 phosphorylation. Most importantly, administration of osimertinib yielded clinical responses in two CD34-high AML patients identified by quantitative proteomics with reduced levels of Y329 phosphorylation of CD34 after treatment. Collectively, these findings delineate a novel molecular pathway whereby EGFR inhibitors kill leukemia and reveal that the CD34 antigen is a targetable signaling molecule that mediates cell survival signals via connecting to Src-STAT3 pathway.

Enhanced expression of EGF receptor in a model of salt-sensitive hypertension

2005 ◽  
Vol 289 (2) ◽  
pp. F314-F321 ◽  
Author(s):  
Wei-Zhong Ying ◽  
Paul W. Sanders
Keyword(s):  
Egf Receptor ◽  
Primary Cultures ◽  
Growth Factor Receptor ◽  
Sprague Dawley ◽  
Renal Vasculature ◽  
Downstream Signaling ◽  
Egfr Expression ◽  
Enhanced Expression

Chronic kidney disease in the Dahl/Rapp salt-sensitive (S) rat is related to an arteriolopathic process that occurs following the onset of hypertension and involves vascular smooth muscle cell (VSMC) hyperplasia and luminal constriction. Because previous studies have shown that activation of the epidermal growth factor receptor (EGFR) produces a mitogenic stimulus in VSMC and the EGFR participates integrally in the vasoconstrictor responses of renal arterioles, the present study analyzed the expression of EGFR in these animals. Compared with Sprague-Dawley (SD) rats, renal cortical expression of EGFR was increased in both prehypertensive and hypertensive S rats. Immunohistochemistry using a polyclonal antibody to EGFR demonstrated that EGFR expression was prominent in the renal vasculature, particularly in the media of afferent and efferent arterioles and the aorta of S rats. When examined, primary cultures of VSMC from S rats showed increased expression of EGFR, compared with VSMC from SD and Dahl/Rapp salt-resistant rats. Following addition of EGF, autophosphorylation of the EGFR was enhanced in cells from S rats, as was the downstream signaling events that included activation of p42/44 MAPK and Akt pathways. Thus in vivo and in vitro studies demonstrated augmented expression and functional activity of the EGFR in S rats.

scholarly journals Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1570 ◽  
Author(s):  
Marija Nešović ◽  
Aleksandra Divac Rankov ◽  
Ana Podolski-Renić ◽  
Igor Nikolić ◽  
Goran Tasić ◽  
...  
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Growth Factor Receptor ◽  
Similar Efficacy ◽  
Src Tyrosine Kinase ◽  
Downstream Signaling ◽  
Egfr Expression ◽  
Human Gbm

Glioblastoma (GBM), as the most aggressive brain tumor, displays a high expression of Src tyrosine kinase, which is involved in the survival, migration, and invasiveness of tumor cells. Thus, Src emerged as a potential target for GBM therapy. The effects of Src inhibitors pyrazolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306 were investigated in human GBM cell lines (U87 and U87-TxR) and three primary GBM cell cultures. Primary GBM cells were more resistant to Si306 and pro-Si306 according to the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. However, the ability of all GBM cells to degrade the extracellular matrix was considerably compromised after Si306 and pro-Si306 applications. Besides reducing the phosphorylation of Src and its downstream signaling pathway components, both compounds decreased the phosphorylated form of focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) expression, showing the potential to suppress the aggressiveness of GBM. In vivo, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model. Considering that Si306 and pro-Si306 are able to cross the blood–brain barrier and suppress the spread of GBM cells, we anticipate their clinical testing in the near future. Moreover, the prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings.

scholarly journals BIOM-22. EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AS A MOLECULAR DETERMINANT OF GLIOBLASTOMA RESPONSE TO DOPAMINE RECEPTOR 2 (DRD2) INHIBITORS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii6-ii6
Author(s):  
Yuyu He ◽  
Jie Li ◽  
Tomoyuki Koga ◽  
Jun Ma ◽  
Sanjay Dhawan ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Ectopic Expression ◽  
Growth Factor Receptor ◽  
Inverse Correlation ◽  
Primary Brain Tumor ◽  
The Cancer Genome Atlas ◽  
Dopamine Synthesis ◽  
Egfr Expression

Abstract BACKGROUND There are ongoing clinical trials exploring the efficacy of dopamine receptor 2 (DRD2) inhibition against glioblastomas, the most common primary brain tumor. Here we examine potential molecular determinants of this efficacy. METHODS The Cancer Genome Atlas (TCGA) glioblastoma database and other published mRNA profiles were used to analyze the DRD2 and EGFR expression pattern. In vitro and in vivo responses to DRD2 inhibitors were determined using patient derived xenograft (PDX) glioblastoma models. Immunohistochemical studies were performed on clinically annotated glioblastoma samples derived from patients treated with ONC201, a DRD2 inhibitor. RESULTS Analysis of clinical glioblastoma specimens derived from independent patient cohorts revealed an inverse correlation between EGFR and DRD mRNA expression, with implication that signaling mediated by these proteins shares overlapping functions. In independent panels of PDX glioblastoma lines, high EGFR expression was associated with poor in vitro and in vivo response to DRD2 inhibitors, including haloperidol and ONC201. Moreover, ectopic expression of a constitutively active EGFR, EGFRvIII, suppressed glioblastoma sensitivity to ONC201. DRD2 expression positively correlated with expression of rate-limiting enzymes for dopamine synthesis as well as dopamine secretion, suggesting contribution of autocrine DRD2 signaling. Analysis of specimens from patients treated with ONC201 (n = 15) showed an inverse correlation between the intensity of EGFR staining and clinical response. The median overall survival for patients with high and low EGFR staining was 162 and 373 days, respectively (p = 0.037). CONCLUSIONS High EGFR expression is a determinant of poor glioblastoma response to DRD2. This finding should inform future clinical trial designs.

scholarly journals The Use of a Non-Conventional Long-Lived Gallium Radioisotope 66Ga Improves Imaging Contrast of EGFR Expression in Malignant Tumours Using DFO-ZEGFR:2377 Affibody Molecule

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 292 ◽  
Author(s):  
Maryam Oroujeni ◽  
Tianqi Xu ◽  
Katherine Gagnon ◽  
Sara S. Rinne ◽  
Jan Weis ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Growth Factor Receptor ◽  
Whole Body ◽  
Malignant Tumours ◽  
Affibody Molecule ◽  
Egfr Expression ◽  
Biodistribution Data ◽  
Positron Emitter

Epidermal growth factor receptor (EGFR) is overexpressed in many malignancies. EGFR-targeted therapy extends survival of patients with disseminated cancers. Radionuclide molecular imaging of EGFR expression would make EGFR-directed treatment more personalized and therefore more efficient. A previous study demonstrated that affibody molecule [68Ga]Ga-DFO-ZEGFR:2377 permits specific positron-emission tomography (PET) imaging of EGFR expression in xenografts at 3 h after injection. We anticipated that imaging at 24 h after injection would provide higher contrast, but this is prevented by the short half-life of 68Ga (67.6 min). Here, we therefore tested the hypothesis that the use of the non-conventional long-lived positron emitter 66Ga (T1/2 = 9.49 h, β+ = 56.5%) would permit imaging with higher contrast. 66Ga was produced by the 66Zn(p,n)66Ga nuclear reaction and DFO-ZEGFR:2377 was efficiently labelled with 66Ga with preserved binding specificity in vitro and in vivo. At 24 h after injection, [66Ga]Ga-DFO-ZEGFR:2377 provided 3.9-fold higher tumor-to-blood ratio and 2.3-fold higher tumor-to-liver ratio than [68Ga]Ga-DFO-ZEGFR:2377 at 3 h after injection. At the same time point, [66Ga]Ga-DFO-ZEGFR:2377 provided 1.8-fold higher tumor-to-blood ratio, 3-fold higher tumor-to-liver ratio, 1.9-fold higher tumor-to-muscle ratio and 2.3-fold higher tumor-to-bone ratio than [89Zr]Zr-DFO-ZEGFR:2377. Biodistribution data were confirmed by whole body PET combined with magnetic resonance imaging (PET/MRI). The use of the positron emitter 66Ga for labelling of DFO-ZEGFR:2377 permits PET imaging of EGFR expression at 24 h after injection and improves imaging contrast.

scholarly journals SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5393
Author(s):  
Sophie Guelfi ◽  
Béatrice Orsetti ◽  
Virginie Deleuze ◽  
Valérie Rigau ◽  
Luc Bauchet ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Growth Factor Receptor ◽  
Treatment Resistance ◽  
Mesenchymal Transition ◽  
Glioblastoma Stem Cell ◽  
A Minor

Glioblastomas (GBM) are high-grade brain tumors, containing cells with distinct phenotypes and tumorigenic potentials, notably aggressive and treatment-resistant multipotent glioblastoma stem cells (GSC). The molecular mechanisms controlling GSC plasticity and growth have only partly been elucidated. Contact with endothelial cells and the Notch1 pathway control GSC proliferation and fate. We used three GSC cultures and glioma resections to examine the expression, regulation, and role of two transcription factors, SLUG (SNAI2) and TAL1 (SCL), involved in epithelial to mesenchymal transition (EMT), hematopoiesis, vascular identity, and treatment resistance in various cancers. In vitro, SLUG and a truncated isoform of TAL1 (TAL1-PP22) were strongly upregulated upon Notch1 activation in GSC, together with LMO2, a known cofactor of TAL1, which formed a complex with truncated TAL1. SLUG was also upregulated by TGF-β1 treatment and by co-culture with endothelial cells. In patient samples, the full-length isoform TAL1-PP42 was expressed in all glioma grades. In contrast, SLUG and truncated TAL1 were preferentially overexpressed in GBMs. SLUG and TAL1 are expressed in the tumor microenvironment by perivascular and endothelial cells, respectively, and to a minor extent, by a fraction of epidermal growth factor receptor (EGFR) -amplified GBM cells. Mechanistically, both SLUG and truncated TAL1 reduced GSC growth after their respective overexpression. Collectively, this study provides new evidence for the role of SLUG and TAL1 in regulating GSC plasticity and growth.

scholarly journals Amphiregulin can predict treatment resistance to palliative first-line cetuximab plus FOLFIRI chemotherapy in patients with RAS wild-type metastatic colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sang-A Kim ◽  
Hyejoo Park ◽  
Kui-Jin Kim ◽  
Ji-Won Kim ◽  
Ji Hea Sung ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Clinical Findings ◽  
Wild Type ◽  
First Line ◽  
Potential Biomarker

AbstractAmphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The aim of this study was to investigate the effects of baseline plasma AREG levels in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The clinical findings were further validated using an in vitro model of CRC. Among 35 patients, the progression-free survival (PFS) was significantly inferior in patients with high AREG than in those with low AREG levels: 10.9 vs. 24.2 months, respectively (p = 0.008). However, after failure of first-line chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab (p < 0.05) via AKT and ERK activation. However, after acquiring cetuximab resistance with gradual exposure for more than 6 months, AREG neither increased colony formation nor activated AKT and ERK after cetuximab treatment. Our results suggest that plasma AREG is a potential biomarker to predict clinical outcomes after cetuximab-based chemotherapy.

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