Epidermal Growth Factor Receptor Blockers Research Articles

Targeted blocking of EGFR and GLUT1 by compound H reveals a new strategy for treatment of triple-negative breast cancer and nasopharyngeal carcinoma

BackgroundCytoplasmic epidermal growth factor receptor (EGFR) is overexpressed in both nasopharyngeal carcinoma (NPC) and triple-negative breast cancer (TNBC), while clinical outcome and prognosis vary greatly among patients treated with gefitinib, and all patients eventually develop resistance to this agent. Therefore, we propose a new concept for synthesizing multitarget compounds and reveal new therapeutic strategies for NPC and TNBC expressing EGFR. MethodsCompound H was synthesized in our previous study. Molecular docking, and cell thermal shift assays (CETSAs) and drug affinity responsive target stability(DARTS) were used to confirm the binding of compound H to EGFR and GLUT1. Methylthiazolyldiphenyl-tetrazolium bromide(MTT), annexin V-PE assays, mitochondrial membrane potential (MMP) assays, and animal models were used to evaluate the inhibitory effect of compound H on TNBC cell lines. Energy metabolism tests, Western blotting, and immunofluorescence staining were performed to evaluate the synergistic effects on EGFR- and glucose transporter type 1(GLUT1)-mediated energy metabolism. ResultsCompound H can simultaneously act on the EGFR tyrosine kinase ATP-binding site and inhibit GLUT1-mediated energy metabolism, resulting in reductions in ATP, MMP, intra-cellular lactic acid, and EGFR nuclear transfer. The anti-tumor activity of compound H is significantly superior to the combination of GLUT1 inhibitor BAY876 and EGFR inhibitor gefitinib. Compound H has remarkable anti-proliferative effects on TNBC MDA-MB231 cells, and importantly, no obvious toxicity effects of compound H were found in vivo. ConclusionsSynergistic effects of inhibition of EGFR- and GLUT1-mediated energy metabolism by compound H may present a new strategy for the treatment of TNBC and NPC.

Targeted Polymeric Nanoparticles as a Strategy for the Treatment of Glioblastoma: A Review.

Glioblastoma multiforme is the most common and aggressive malignant tumor that affects the central nervous system, with high mortality and low survival. Glioblastoma multiforme treatment includes resection tumor surgery, followed by radiotherapy and chemotherapy adjuvants. However, the drugs used in chemotherapy present some limitations, such as the difficulty of crossing the bloodbrain barrier and resisting the cellular mechanisms of drug efflux. The use of polymeric nanoparticles has proven to be an effective alternative to circumvent such limitations, as it allows the exploration of a range of polymeric structures that can be modified in order to control the biodistribution and cytotoxic effect of the drug delivery systems. Nanoparticles are nanometric in size and allow the incorporation of targeting ligands on their surface, favoring the transposition of the blood-brain barrier and the delivery of the drug to specific sites, increasing the selectivity and safety of chemotherapy. The present review has described the characteristics of chitosan, poly(vinyl alcohol), poly(lactic-coglycolic acid), poly(ethylene glycol), poly(β-amino ester), and poly(ε-caprolactone), which are some of the most commonly used polymers in the manufacture of nanoparticles for the treatment of glioblastoma multiforme. In addition, some of the main targeting ligands used in these nanosystems are presented, such as transferrin, chlorotoxin, albumin, epidermal growth factor, and epidermal growth factor receptor blockers, explored for the active targeting of antiglioblastoma agents.

Intravitreal panitumumab for prevention of myopic axial elongation in highly myopic adult eyes with myopic macular degeneration: Phase 1 study on safety

AbstractPurpose: Recent histomorphometric and clinical studies suggested that axial myopic elongation occurs through an enlargement of Bruch's membrane (BM) in the retroequatorial and equatorial region, leading to a thinning of choroid and sclera at the posterior pole. Thickness of the retina and choriocapillaris and RPE‐density in the macular region and BM thickness in any region remain independent of axial length. The equatorial‐to‐retroequatorial BM enlargement may be caused by an epidermal growth factor (EGF)‐associated RPE activity. Experimental studies in guinea pigs and monkeys showed a reduction in axial elongation by intravitreally applied blockers of EGF family members and the EGF receptor, and an increase in axial elongation by intravitreally applied EGF family members. In a clinical study, the intraocular EGF amount correlated with longer axial length. It led to the hypothesis, that ocular axial elongation is associated with EGF, and that further axial elongation may be prevented by an EGF blockade. We examined here the safety of intravitreally applied panitumumab, an EGF receptor blocker, already in clinical systemic use in oncology for two decades.Methods: The phase‐1 study included highly myopic adult patients with myopic macular degeneration. The eyes received one to two intravitreal injections of 0.6 mg (60 μl), 1.2 mg (120 μl) or 1.8 mg (180 μl) panitumumab.Results: The study included 10 patients (age 57–72 years, axial length: 29.10 mm–32.67 mm). Examined at day 1, 7, and 28 and at 2 and 3 months after the injections, the injected eyes did not show any intraocular inflammation or morphologic or functional changes, assessed by retinal electroretinography, perimetry, optical coherence tomography, tonometry and visual acuity measurement.Conclusions: The preliminary observations of these 10 patients are in agreement with a notion of an intraocular tolerability of panitumumab repeatedly injected intravitreally in doses of 0.6, 1.2 or 1.8 mg.

Short-course pembrolizumab and continuous afatinib therapy for recurrent or metastatic head and neck squamous cell carcinoma: a real-world data analysis

ObjectivesThe optimal duration of anti-PD-1 for cancer therapy has not been tested, especially when using combination therapy. Epidermal growth factor receptor (EGFR) pathway blocker was the top compound that enhanced T-cell killing of tumor cells in a high-throughput immune-oncology screen, possibly by stimulate the antigen presentation machinery and other mechanisms. We explored the effect of combination of EGFR inhibition with a short course of anti-PD-1 therapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC).MethodWe analyzed the effect of a short course of anti-PD-1 with continuous afatinib on the survival of a real-world cohort of R/M HNSCC patients. Patient characteristics, treatments, efficacies, and toxicities were reviewed and recorded for analysis.ResultsFrom November 2016 to May 2018, 51 consecutive patients received pembrolizumab and afatinib. The cutoff date was June 30, 2022. The most common toxicities (all grades) were diarrhea (62.7%), skin rash (43.1%), mucositis (31.4%), and paronychia (23.5%). The objective response rate was 54.9% (95% confidence interval [CI] 40.3–68.9%). Median progression-free survival was 5.9 months (95% CI: 4.4–7.6 months), and the median overall survival was 10.5 months (95% CI: 6.8–16.5 months). The 12-month, 24-month, 36-month, and 48-month survival rate was 47.0%, 22.5%, 17.7%, and 12.6% respectively.ConclusionsThis retrospective study showed that short course pembrolizumab with afatinib therapy has acceptable efficacy in R/M HNSCC patients. The durable response and long-term survival rates were similar to prospective clinical trials. Short course anti-PD-1 therapy, especially in combination with EGFR blocker, is worth for further prospective study.

EXTH-36. MRGFUS-DELIVERED FLUORESCENT EGFR/EGFRVIII ANTIBODY ENABLES THERANOSTIC IMAGING OF PEDIATRIC HIGH-GRADE GLIOMA AND PREDICTS RESPONSE TO TARGETED THERAPY

Abstract BACKGROUND Pediatric high-grade glioma (pHGG) consists of the deadliest childhood brain cancers refractory to current therapies. Fluorescent antibodies against epidermal growth factor receptor (EGFR) have demonstrated clinical promise in image-guided surgery of adult gliomas. However, their potential theranostic use for pHGG remains unexamined. This study evaluated an EGFR/EGFRvIII-targeted imaging and treatment strategy as an alternative therapeutic approach for pHGG using tracer amount of fluorescent antibody delivered through blood-brain barrier modulation. METHODS Immunohistochemical stainings of EGFR, EGFRvIII and claudin-5 were performed on pHGG patient tissue (n = 66). In vitro competition assay assessed binding affinity of panitumumab-IRDye800 for EGFR/EGFRvIII on pHGG cells whose viability was measured upon panitumumab treatment. Mice with EGFR/EGFRvIII-positive orthotopic pHGG patient-derived xenografts received 1 mg/kg panitumumab-IRDye800 20 hours after transcranial magnetic resonance-guided focused ultrasound (MRgFUS) sonication (2 min at 0.25 MPa). Near-infrared fluorescence imaging measured tumor-to-background ratio and TUNEL assay determined apoptotic rate in resected tumor. Survival was documented for 60 days in pHGG-bearing mice receiving 1 mg/kg panitumumab weekly with or without MRgFUS. RESULTS 61% and 24% pHGG patient tissue respectively expressed EGFR and EGFRvIII (17% expressing both). Heterogeneous claudin-5 expression indicated partial blood-brain barrier permeability. Panitumumab-IRDye800 bound to EGFR/EGFRvIII-positive pHGG with high affinity (IC50: 4.2 nM). EGFR blocking enhanced therapeutic response of panitumumab by 48 ± 13%. Following MRgFUS in pHGG-bearing mice, 19 ± 6.3% injected dose of intratumoral panitumumab-IRDye800 uptake resulted in 2.1 ± 0.4 tumor contrast and 3.9 ± 1.1% apoptotic cell death. Weekly MRgFUS with 1 mg/kg panitumumab prolonged median survival (27.5 vs. 17.5 days, P < 0.0001, n = 10). CONCLUSION Tracer dose of panitumumab-IRDye800 improved tumor contrast and predicted antitumor activity via EGFR/EGFRvIII dual targeting following MRgFUS, potentially benefiting 68% of pHGG population. Reduced therapeutic dose of panitumumab by EGFRvIII-focused targeting may improve treatment safety and efficacy against EGFRvIII-stratified gliomas.

EGFR-Targeted Perfluorohexane Nanodroplets for Molecular Ultrasound Imaging.

Perfluorocarbon nanodroplets offer an alternative to gaseous microbubbles as contrast agents for ultrasound imaging. They can be acoustically activated to induce a liquid-to-gas phase transition and provide contrast in ultrasound images. In this study, we demonstrate a new strategy to synthesize antibody-conjugated perfluorohexane nanodroplet (PFHnD-Ab) ultrasound contrast agents that target cells overexpressing the epidermal growth factor receptor (EGFR). The perfluorohexane nanodroplets (PFHnD) containing a lipophilic DiD fluorescent dye were synthesized using a phospholipid shell. Antibodies were conjugated to the surface through a hydrazide-aldehyde reaction. Cellular binding was confirmed using fluorescence microscopy; the DiD fluorescence signal of the PFHnD-Ab was 5.63× and 6× greater than the fluorescence signal in the case of non-targeted PFHnDs and the EGFR blocking control, respectively. Cells were imaged in tissue-mimicking phantoms using a custom ultrasound imaging setup consisting of a high-intensity focused ultrasound transducer and linear array imaging transducer. Cells with conjugated PFHnD-Abs exhibited a significantly higher (p < 0.001) increase in ultrasound amplitude compared to cells with non-targeted PFHnDs and cells exposed to free antibody before the addition of PFHnD-Abs. The developed nanodroplets show potential to augment the use of ultrasound in molecular imaging cancer diagnostics.

Hypoxic pulmonary endothelial cells release epidermal growth factor leading to vascular smooth muscle cell arginase-2 expression and proliferation.

The hallmark of pulmonary hypertension (PH) is vascular remodeling. We have previously shown that human pulmonary microvascular endothelial cells (hPMVEC) respond to hypoxia with epidermal growth factor (EGF) mediated activation of the receptor tyrosine kinase, EGF receptor (EGFR), resulting in arginase‐2 (Arg2)‐dependent proliferation. We hypothesized that the release of EGF by hPMVEC could result in the proliferation of human pulmonary arterial smooth muscle cells (hPASMC) via activation of EGFR on the hPASMC leading to Arg2 up‐regulation. To test this hypothesis, we used conditioned media (CM) from hPMVEC grown either in normoxia (NCM) or hypoxia (HCM). Human PASMC were incubated in normoxia with either HCM or NCM, and HCM caused significant induction of Arg2 and viable cell numbers. When HCM was generated with either an EGF‐neutralizing antibody or an EGFR blocking antibody the resulting HCM did not induce Arg2 or increase viable cell numbers in hPASMC. Adding an EGFR blocking antibody to HCM, prevented the HCM‐induced increase in Arg2 and viable cell numbers. HCM induced robust phosphorylation of hPASMC EGFR. When hPASMC were transfected with siRNA against EGFR the HCM‐induced increase in viable cell numbers was prevented. When hPASMC were treated with the arginase antagonist nor‐NOHA, the HCM‐induced increase in viable cell numbers was prevented. These data suggest that hypoxic hPMVEC releases EGF, which activates hPASMC EGFR leading to Arg2 protein expression and an increase in viable cell numbers. We speculate that EGF neutralizing antibodies or EGFR blocking antibodies represent potential therapeutics to prevent and/or attenuate vascular remodeling in PH associated with hypoxia.

EGFR blocker lapatinib inhibits the synthesis of matrix metalloproteinases from synovial fibroblasts.

Epidermal growth factor receptor (EGFR) family members and their associated ligands may be related to bone and joint destruction in rheumatoid arthritis. Matrix metalloproteinases are responsible for joint and bone tissue degradation. This study is intended to investigate the effect of epidermal growth factor receptor inhibition by lapatinib on the synthesis of matrix metalloproteinases in in vitro. Synovial fibroblast cell culture was obtained from a patient with rheumatoid arthritis who underwent knee arthroplasty. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were added to the cell culture to stimulate synovial fibroblast cells and create an inflammatory character. Understimulated and nonstimulated conditions, lapatinib was applied to the culture in four different concentrations of 25, 50, 100, and 200 µmol. Then, matrix metalloproteinase -1, -3, and, -13 levels were assessed. When stimulated with IL-1β and TNF-α, the synthesis of matrix metalloproteinases from synovial fibroblast was increased significantly. When lapatinib is added to the stimulated synovial fibroblasts, matrix metalloproteinases synthesis is significantly suppressed. Inhibition of the EGFR pathway with lapatinib suppresses matrix metalloproteinases synthesis. Our results suggest EGFR pathway inhibition may be a promising option to prevent joint destruction in the treatment of rheumatoid arthritis.

Dysfunctional EGFR and oxidative stress-induced PKD1 signaling drive formation of DCLK1+ pancreatic stem cells

SummaryDoublecortin-like kinase 1 (DCLK1)-positive pancreatic cancer stem cells develop at a precancerous stage and may contribute to the lack of efficacy of pancreatic cancer therapy. Although PanIN cells express oncogenic KRas and have an increased activity of epidermal growth factor receptor (EGFR), we demonstrate that, in DCLK1+ PanIN cells, EGFR signaling is not propagated to the nucleus. Mimicking blockage of EGFR with erlotinib in PanIN organoid culture or in p48cre;KrasG12D mice led to a significant increase in DCLK1+ PanIN cells. As a mechanism of how EGFR inhibition leads to formation of DCLK1+ cells, we identify an increase in hydrogen peroxide contributing to activation of Protein Kinase D1 (PKD1). Active PKD1 then drives stemness and abundance of DCLK1+ cells in lesions. Our data suggest a signaling mechanism that leads to the development of DCLK1+ pancreatic cancer stem cells, which can be exploited to target this population in potential therapeutic approaches.

Epidermal growth factor promotes stromal cells migration and invasion via up-regulation of hyaluronate synthase 2 and hyaluronan in endometriosis

To investigate the role(s) of hyaluronan synthase 2 (HAS2) and hyaluronan in disease progression of endometriosis and epidermal growth factor (EGF)-induced motility changes of endometriotic cells. A case-control experimental study and invitro primary cell culture study. University hospital-affiliated research centers. A total of 21 women with stage I/II endometriosis, 33 women with stage III/IV endometriosis with endometrioma, and 32 women without endometriosis were included in our study. Serum, eutopic endometrial tissues, and/or ectopic endometriotic tissues were collected. Primary eutopic endometrial stromal cells (EuESCs) and ectopic ovarian endometriotic stromal cells (OvESCs) were isolated and cultured from women with ovarian endometrioma, and then treated with or without EGF. The concentrations of EGF and hyaluronan in serum were analyzed by enzyme-linked immunosorbent assay. The expressions and localizations of EGF receptor (EGFR), phosphorylated-(p)EGFR, HAS2, and hyaluronan receptor CD44 in tissues were examined by immunohistochemistry. The mRNA and protein levels of HAS2 in EuESCs and OvESCs were examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot, respectively, and the concentrations of hyaluronan in conditioned medium were examined by enzyme-linked immunosorbent assay (ELISA). Cell motility was evaluated by transwell migration/invasion assays. Serum EGF and hyaluronan concentrations were higher in women with stage III/IV endometriosis than in women with stage I/II or without endometriosis. EGFR, pEGFR, HAS2, and CD44 were immunolocalized in eutopic endometrium and ectopic endometriotic lesions, and the expressions of pEGFR and HAS2 were elevated in ectopic endometriotic lesions compared to eutopic endometrium. Treatment with EGF upregulated HAS2 and hyaluronan expression as well as cell migration and invasion in both EuESCs and OvESCs, and pharmaceutical blocking of EGFR abolished these effects. In addition, knockdown of HAS2 by small interfering RNA attenuated both basal and EGF-induced hyaluronan expression and cell motility changes. Notably, ERK1/2 and AKT signaling pathways were shown to be downstream of EGF in regulating HAS2 and hyaluronan expression as well as cell migration and invasion. EGF increased the expression of endometriosis-associated hyaluronan and its synthase HAS2, both of which mediated EGF-induced stromal cell migration and invasion in women with endometriosis.

NT5DC2 promotes tumor cell proliferation by stabilizing EGFR in hepatocellular carcinoma

Most hepatocellular carcinoma (HCC) patients are diagnosed at an advanced stage; however, the effect of systemic therapy on advanced HCC remains undetermined. Therefore, new treatment targets must be identified. We analyzed Gene Expression Omnibus datasets from two HCC patient cohorts and found that NT5DC2 was associated with vascular invasion and poor survival. In two hepatoma cell lines, NT5DC2 overexpression promoted HCC cell proliferation and clone formation in vitro and promoted tumor growth in vivo. Coimmunoprecipitation assays and liquid chromatography with tandem mass spectrometry analysis revealed that NT5DC2 bound directly to epidermal growth factor receptor (EGFR). NT5DC2 upregulated EGFR expression by downregulating EGFR ubiquitination and preventing its degradation via the ubiquitin-proteasome pathway but did not upregulate its transcription. EGFR upregulation activated downstream signal transduction, which played a critical role in the protumor effects of NT5DC2. Erlotinib, a small-molecule inhibitor of EGFR, blocked the effect of NT5DC2 in promoting HCC cell proliferation. In a cohort of 79 patients who underwent curative resection for HCC, NT5DC2 expression in the tumors was associated with larger tumors and microvascular invasion. NT5DC2 expression was also independently associated with recurrence-free survival. The present study demonstrated for the first time that NT5DC2 promotes tumor cell proliferation in HCC and may serve as a potential molecular target for treating HCC. EGFR blockage could be used to treat selected patients with NT5DC2 upregulation.

Systematic Comparison of Label-Free, SILAC, and TMT Techniques to Study Early Adaption toward Inhibition of EGFR Signaling in the Colorectal Cancer Cell Line DiFi.

We evaluated the quantification strategies label-free (LF), stable isotope labeling by amino acids in cell culture (SILAC), and tandem mass tags (TMT) and their performance in quantification of proteins and phosphosites (p-sites) to identify the most powerful approach for monitoring cellular signaling. We analyzed the epidermal growth factor receptor (EGFR) signaling network, which plays an essential role in colorectal cancer, and studied its dynamics within 24 h upon treatment with the EGFR-blocking antibody cetuximab, representing the first cellular adaption toward therapy. LF achieved superior coverage but was outperformed by label-based approaches regarding technical variability, especially for quantification of p-sites. TMT showed the lowest coverage and most missing values. We found that its performance considerably decreases when experimental replicates are distributed over several TMT plexes. SILAC showed the highest precision and outstanding performance for quantification of p-sites, rendering it the method of choice for analyzing cellular signaling in cell culture models. On the protein level, we observed only little regulation upon cetuximab treatment, whereas a great fraction of p-sites was significantly regulated. These dynamics represented an initial downregulation of the MAPK pathway, which was partially rescued as early as 24 h after treatment. We identified upregulation and signaling via ERBB3 as well as calcium and cAMP signaling as possible mechanisms bypassing the blockage of EGFR.

What are the benefits and harms of epidermal growth factor receptor blockers for the treatment of relapsed ovarian cancer?

What are the benefits and harms of epidermal growth factor receptor blockers for the treatment of relapsed ovarian cancer?

What are the benefits and harms of epidermal growth factor receptor (EGFR) blockers for the treatment of ovarian cancer after first-line therapy?

What are the benefits and harms of epidermal growth factor receptor (EGFR) blockers for the treatment of ovarian cancer after first-line therapy?

Developing a Novel and Convenient Model for Investigating Sweat Gland Morphogenesis from Epidermal Stem Cells.

Sweat glands developed from the embryonic epidermis. To elucidate the underlying mechanisms of morphogenesis, a reliable in vitro test system for bioactive screening must be developed. Here, we described a novel and convenient model by coculturing embryonic tissue and epidermal stem cells (ESCs) using Transwell insert for evaluating the effects of soluble morphogens on sweat gland morphogenesis in vitro. Using this coculture system, morphological alteration, histological features, and specific markers were observed. Initial experiments revealed that ESCs cocultured with embryonic paw pad (EPP) tissue demonstrated glandular structure and cytokeratin 8 (K8) and cytokeratin 18 (K18) positive, while ESCs cocultured with embryonic dorsal skin demonstrated “sea snail” structure and K8, K18 negative. Moreover, bone morphogenetic protein 4 (BMP4) and epidermal growth factor (EGF) concentrations were detected in the medium of the EPP group. BMP receptor inhibitor could effectively block the ESC differentiation to sweat glands, while EGF receptor blocker did not show the effect. Our results showed clear benefits of this novel and convenient model in terms of in vitro-in vivo correlation. It was an appropriate alternative for screening of potential bioactives regulating the sweat gland morphogenesis mechanism.

Effect of Cetuximab on the Development of Epidural Fibrosis Based on CD105 and Osteopontin Immunohistochemical Staining

The effect of cetuximab on the development of epidural fibrosis (EF) was assessed using immunohistochemical methods as well as antibodies for CD105 and osteopontin (OPN). The goal of this study was to assess of EGFR inhibition for the postoperative treatment of fibrosis. EF is one of most common causes of failed back surgery syndrome, which occurs after laminectomy. Numerous causes and mechanisms have been proposed to explain its development after laminectomy. Many agents have been tested to prevent the development of EF. EGFR, a multi-functional transmembrane glycoprotein, causes cell growth, proliferation, and EF by interacting with epidermal growth factor and TGF-β1. The inhibition of postoperative fibrosis using cetuximab, an epidermal growth factor receptor blocker, is theoretically possible. However, this has not been tested to date. Sixteen Wistar-Albino rats were divided into two groups, namely, control and cetuximab groups. L1-2 laminectomy alone was performed in both groups, and topical cetuximab was applied to the treatment group. After 6 weeks, rats were sacrificed and examined histopathologically and immunohistochemically; EF tissue was also graded. Statistical significance was accepted at P < 0.05. Fibroblast counts and fibrosis density, determined by histopathologic examination, and EF, according to immunohistochemical assessment based on CD105, were found to be higher in the treatment group than in the control group, and this was statistically significant (P < 0.001). Based on OPN staining, the results were consistent with classical methods, and no significant difference was detected among the groups (P = 0.358). Our study revealed that cetuximab inhibits the development of EF and that CD105, and not OPN, is a reliable marker for grading EF. In addition, cetuximab did not result in toxic, systemic side effects in surrounding tissues. N/A.

Synthesis of Triazole-Substituted Quinazoline Hybrids for Anticancer Activity and a Lead Compound as the EGFR Blocker and ROS Inducer Agent.

A series of triazole-substituted quinazoline hybrid compounds were designed and synthesized for anticancer activity targeting epidermal growth factor receptor (EGFR) tyrosine kinase. Most of the compounds showed moderate to good antiproliferative activity against four cancer cell lines (HepG2, HCT116, MCF-7, and PC-3). Compound 5b showed good antiproliferative activity (IC50 = 20.71 μM) against MCF-7 cell lines. Molecular docking results showed that compound 5b formed hydrogen bond with Met 769 and Lys 721 and π–sulfur interaction with Met 742 of EGFR tyrosine kinase (PDB ID: 1M17). Compound 5b decreases the expression of EGFR and p-EGFR. It also induces apoptosis through reactive oxygen species generation, followed by the change in mitochondrial membrane potential.

Epidermal growth factor receptor blockers for the treatment of ovarian cancer.

This is an update of a previously published version of the review (Issue 10, 2011).Epithelial ovarian cancer (EOC) is the seventh most common cause of cancer death among women worldwide. Treatment consists of a combination of surgical debulking and platinum-based chemotherapy. Between 55% and 75% of women who respond to first-line therapy experience relapse within twoyears. Second-line chemotherapy is palliative and aims to reduce symptoms and prolong survival. Improved understanding about the molecular basis of EOC has led to the development of novel agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and anti-EGFR antibodies. To compare the effectiveness and harmful effects of interventions that target the epidermal growth factor receptor in the treatment of epithelial ovarian cancer (EOC). We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2010, Issue 4), MEDLINE, and Embase up to October 2010. We also searched registers of clinical trials, abstracts of scientific meetings, and reference lists of included studies, and we contacted experts in the field. This update includes further searches up to September 2017. Randomised controlled trials (RCTs) comparing anti-EGFR agents with or without conventional chemotherapy versus conventional chemotherapy alone or no treatment in women with histologically proven EOC. Two review authors independently abstracted data, assessed risk of bias, and performed GRADE assessment. From 6105 references obtained through the literature search and an additional 15 references derived from grey literature searches, we identified seven RCTs that met our inclusion criteria and included 1725 participants. Trial results show that after first-line chemotherapy is provided, maintenance treatment with erlotinib (EGFR tyrosine kinase inhibitor (TKI)) probably makes little or no difference in overall survival (hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.81 to 1.20; one study; 835 participants; low-certainty evidence) and may make little or no difference in progression-free survival (HR 1.05, 95% CI 0.90 to 1.23; one study; 835 participants; very low-certainty evidence). Less than 50% of participants provided quality of life data, and study authors reported these results incompletely. The certainty of evidence is very low, but treatment may reduce quality of life compared to observation.Treatment with an EGFR TKI (vandetanib) for women with relapsed EOC may make little or no difference in overall survival (HR 1.25, 95% CI 0.80 to 1.95; one study; 129 participants; low-certainty evidence) and may make little or no difference in progression-free survival (HR 0.99, 95% CI 0.69 to 1.42; one study; 129 participants; very low-certainty evidence). In treating patients with relapse, giving EGFR TKI may slightly increase some toxicities, such as severe rash (risk ratio (RR) 13.63, 95% CI 0.78 to 236.87; one study; 125 participants; very low-certainty evidence). Quality of life data were not available for meta-analysis.Anti-EGFR antibody treatment in relapsed EOC may or may not make a difference to overall survival (HR 0.93, 95% CI 0.74 to 1.18; four studies; 658 participants; moderate-certainty evidence) and may or may not have any effect on progression-free survival (HR 0.90, 95% CI 0.70 to 1.16; four studies; 658 participants; low-certainty evidence). Anti-EGFR antibody treatment may or may not increase side effects, including severe nausea and/or vomiting (RR 1.27, 95% CI 0.56 to 2.89; three studies; 503 participants; low-certainty evidence), severe fatigue (RR 1.06, 95% CI 0.66 to 1.73; I² = 0%; four studies; 652 participants; low-certainty evidence), and hypokalaemia (RR 2.01, 95% CI 0.80 to 5.06; I² = 0%; three studies; 522 participants; low-certainty evidence). Severe diarrhoea rates were heterogeneous across studies (RR 2.87, 95% CI 0.59 to 13.89; four studies; 652 participants; low-certainty evidence), and subgroup analysis revealed that severe diarrhoea was more likely with pertuzumab (RR 6.37, 95% CI 1.89 to 21.45; I² = 0%; three studies; 432 participants; low-certainty evidence) than with seribantumab treatment (RR 0.38, 95% CI 0.07 to 2.23; I² = 0%; one study; 220 participants; very low-certainty evidence). Quality of life data were incompletely reported, and we were unable to combine them in a meta-analysis. Current evidence suggests that an anti-EGFR single-agent biological treatment (EGFR TKI or anti-EGFR antibody) makes little or no difference to survival, either as maintenance treatment after first-line chemotherapy or in association with chemotherapy in recurrent cancer. Anti-EGFR therapy may increase some side effects and may or may not reduce quality of life.

NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest

Notch dysregulation has been implicated in numerous tumors, including triple-negative breast cancer (TNBC), which is the breast cancer subtype with the worst clinical outcome. However, the importance of individual receptors in TNBC and their specific mechanism of action remain to be elucidated, even if recent findings suggested a specific role of activated-Notch3 in a subset of TNBCs. Epidermal growth factor receptor (EGFR) is overexpressed in TNBCs but the use of anti-EGFR agents (including tyrosine kinase inhibitors, TKIs) has not been approved for the treatment of these patients, as clinical trials have shown disappointing results. Resistance to EGFR blockers is commonly reported. Here we show that Notch3-specific inhibition increases TNBC sensitivity to the TKI-gefitinib in TNBC-resistant cells. Mechanistically, we demonstrate that Notch3 is able to regulate the activated EGFR membrane localization into lipid rafts microdomains, as Notch3 inhibition, such as rafts depletion, induces the EGFR internalization and its intracellular arrest, without involving receptor degradation. Interestingly, these events are associated with the EGFR tyrosine dephosphorylation at Y1173 residue (but not at Y1068) by the protein tyrosine phosphatase H1 (PTPH1), thus suggesting its possible involvement in the observed Notch3-dependent TNBC sensitivity response to gefitinib. Consistent with this notion, a nuclear localization defect of phospho-EGFR is observed after combined blockade of EGFR and Notch3, which results in a decreased TNBC cell survival. Notably, we observed a significant correlation between EGFR and NOTCH3 expression levels by in silico gene expression and immunohistochemical analysis of human TNBC primary samples. Our findings strongly suggest that combined therapies of TKI-gefitinib with Notch3-specific suppression may be exploited as a drug combination advantage in TNBC treatment.

Effects of Cetuximab and Erlotinib on the behaviour of cancer stem cells in head and neck squamous cell carcinoma

The therapeutic responses of many solid tumours to chemo- and radio-therapies are far from fully effective but therapies targeting malignancy-related cellular changes show promise for further control. In head and neck squamous cell carcinoma, the epidermal growth factor receptor (EGFR) is commonly overexpressed and investigation of agents that block this receptor indicate a limited response when used alone but an ability to enhance the actions of other drugs. The hierarchical stem cell patterns present in tumours generate cellular heterogeneity and this is further complicated by cancer stem cells (CSC) shifting between epithelial (Epi-CSC) and mesenchymal (EMT-CSC) states. To clarify how such heterogeneity influences responses to EGFR blocking, we examined the effects of Cetuximab and Erlotinib on the cell sub-populations in HNSCC cell lines. These agents reduced cell proliferation for all subpopulations but induced little cell death. They did however induce large shifts of cells between the EMT-CSC, Epi-CSC and differentiating cell compartments. Loss of EMT-CSCs reduced cell motility and is expected to reduce invasion and metastasis. EGFR blocking also induced shifts of Epi-CSCs into the differentiating cell compartment which typically has greater sensitivity to chemo/radiation, an effect expected to enhance the overall response of tumour cell populations to adjunctive therapies.