Epidermal Growth Factor Receptor Signaling Pathway Research Articles

Epidermal growth factor receptor antagonists in colorectal cancer: emerging strategies for precision therapy.

The global prevalence of colorectal cancer highlights the need to enhance treatment strategies for improved patient outcomes. The pivotal role of epidermal growth factor receptor (EGFR) signaling in regulating cellular processes for this disease pinpoints its value as a therapeutic target, despite the emergence of resistance mechanisms over time. This review discusses the clinical evidence supporting the use of EGFR inhibitors in molecularly-selected patients based on molecular characteristics (notably BRAF V600E and KRAS G12C) including combination approaches targeting different points in in the signaling pathway, as well as strategies such as EGFR inhibitor rechallenge. The role of HER2 inhibitors and emerging approaches such as bispecific antibodies are also reviewed. Recently, inhibitors targeting the KRAS G12C variant have emerged, albeit with modest monotherapy activity compared to other tumor types, emphasizing the influence of histologic origins on the EGFR signaling pathway. Integration of EGFR inhibitors into precision medicine has facilitated tailored therapies addressing resistance mechanisms. Patient selection for EGFR inhibitor rechallenge guided by ctDNA findings is crucial, with ongoing investigations exploring novel combinations to enhance EGFR blockade, highlighting the transformative potential of precision medicine in shaping the future of mCRC treatment toward personalized and targeted approaches.

EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma.

The prognosis for metastatic gastric adenocarcinoma (mGAC) remains poor. Gene alterations in receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and their downstream effectors including catalytic subunit alpha of the phosphatidylinositol 3-kinase (PIK3CA) are common in mGAC. Targeted RTK and phosphatidylinositol-3-kinase (PI3K) treatments have demonstrated clinical benefits in other solid tumours and are key potential targets for clinical development against mGAC given the presence of recurrent alterations in these pathways. Furthermore, combination RTK/PI3K treatments may overcome compensatory mechanisms that arise using monotherapies, leading to improved patient outcomes. Herein, we investigated RTK/PI3K single and combination drug responses against our unique human mGAC-derived PIK3CA gain-of-function mutant, human epidermal growth factor receptor 2 (HER2)-negative, EGFR-expressing circulating tumour cell line, UWG02CTC, under two- and three-dimensional culture conditions to model different stages of metastasis. UWG02CTCs were highly responsive to the PI3K p110α-subunit targeted drugs PIK-75 (IC50 = 37.0 ± 11.1 nM) or alpelisib (7.05 ± 3.7 µM). Drug sensitivities were significantly increased in 3D conditions. Compensatory MAPK/ERK pathway upregulation by PI3K/Akt suppression was overcome by combination treatment with the EGFR inhibitor gefitinib, which was strongly synergistic. PIK-75 plus gefitinib significantly impaired UWG02CTC invasion in an organotypic assay. In conclusion, UWG02CTCs are a powerful ex vivo mGAC drug responsiveness model revealing EGFR/PI3K-targeted drugs as a promising combination treatment option for HER2-negative, RAS wild-type mGAC patients.

The involvement of epidermal growth factor receptor/protein kinase Bsignaling in the tumor intrinsic PD-L1-induced malignant potential of oral squamous cell carcinoma.

Various antigen-presenting cells and tumor cells-expressing PD-L1 inhibits antitumor immune responses in the tumor microenvironment. Recently, numerous studies have shown that tumor cell intrinsic PD-L1 also plays important roles in tumor growth and progression. On the other hand, oral squamous cell carcinoma (OSCC) cells overexpress epidermal growth factor receptor (EGFR) and EGFR signal pathway exacerbates tumor progression. Therefore, this study assessed whether tumor-intrinsic PD-L1 facilitates malignant potential of OSCC cells through regulation of EGFR signaling. Two OSCC cell lines, SAS and HSC-3, were transfected with PD-L1 and EGFR-specific small interfering RNA (siRNA). Influences of PD-L1 knockdown on malignant potentials of OSCC cells were examined by Cell Counting kit-8 assay, transwell assay, sphere formation assay, flow cytometry, and Western blot. Effects of PD-L1 and EGFR knockdown on each expression were examined by quantitative real-time PCR (qRT-PCR), Western blot, and flow cytometry. Transfection of an PD-L1-siRNA into OSCC cells decreased the abilities of proliferation, stemness, and mobility of these cells significantly. PD-L1 knockdown also decreased EGFR expression through the promotion of proteasome- and lysosome-mediated degradation and following activation of the EGFR/protekin kinase B (AKT)signal pathway. Meanwhile, EGFR knockdown did not influence PD-L1 expression in SAS and HSC-3 cells, but treatment with a recombinant human EGF induced its expression. Treatment with erlotinib and cetuximab suppressed rhEGF-induced PD-L1 expression and localization in the cellular membrane of both OSCC cells. OSCC cells-expressing PD-L1 induced by EGF stimulation may promote malignancy intrinsically via the activation of the EGFR/AKT signaling cascade.

“Qi Nan” agarwood restores podocyte autophagy in diabetic kidney disease by targeting EGFR signaling pathway

BackgroundDiabetic kidney disease (DKD) is a microvascular complication of diabetes mellitus, contributing to end-stage renal disease with limited treatment options. The development of DKD is attributed to podocyte injury resulting from abnormal podocyte autophagy. Consequently, the restoration of podocyte autophagy is deemed a practicable approach in the treatment of DKD.MethodsDiabetic mice were induced by streptozotocin and high-fat diet feeding. Following 8 weeks of “QN” agarwood treatment, metrics such as albuminuria, serum creatinine (Scr), and blood urea nitrogen (BUN) were evaluated. Renal histological lesions were evaluated by H&E, PAS, Masson, and Sirius red staining. Evaluation of the effects of “QN” agarwood on renal inflammation and fibrosis in DKD mice through WB, q-PCR, and IHC staining analysis. Cytoscape 3.7.1 was used to construct a PPI network. With the DAVID server, the gene ontology (GO) functional annotation and the Kyoto encyclopedia of genes and genomes (KEGG) signaling pathways of the target enrichment were performed. Molecular docking and binding affinity calculations were conducted using AutoDock, while PyMOL software was employed for visualizing the docking results of active compounds and protein targets.ResultsThe results of this study show that “QN” agarwood reduced albuminuria, Scr, and BUN in DKD mice, and improved the renal pathological process. Additionally, “QN” agarwood was observed to downregulate the mRNA and protein expression levels of pro-inflammatory and pro-fibrotic factors in the kidneys of DKD mice. Network pharmacology predicts that “QN” agarwood modulates the epidermal growth factor receptor (EGFR) signaling pathway. “QN” agarwood can increase the expression of LC3B and Nphs1 in DKD mice while reducing the expression of EGFR.ConclusionThe present study demonstrated that “QN” agarwood ameliorated renal injury in DKD by targeting EGFR and restoring podocyte autophagy.Graphical

Chemical Scaffolds for the Clinical Development of Mutant-Selective and Reversible Fourth-Generation EGFR-TKIs in NSCLC.

In nonsmall cell lung cancer (NSCLC), as well as in other tumors, the targeted therapy is mainly represented by tyrosine kinase inhibitors (TKIs), small molecules able to target oncogenic driver alterations affecting the gene encoding the epidermal growth factor receptor (EGFR). Up to now, several different TKIs have been developed. However, cancer cells showed an incredible adaptive tumor response to the inhibition of the sequentially mutated EGFR (EGFRM+), triggering the need to explore novel pharmacochemical strategies. This Review summarizes the recent efforts in the development of new reversible next-generation EGFR TKIs to fight the resistance against T790M and C797S mutations. Specifically, after giving an overview of the role of the EGFR's signaling pathways in cancer progression, we are going to discuss the most relevant approved drugs and drug candidates in terms of chemical structure, binding modalities, and their potency and selectivity against the mutated EGFR over the wild-type form. This could provide important guidelines and rationale for the discovery and iterative development of new drugs.

Abstract 6005: Generation of new oncology cell models through long-term acclimation under hypoxic and hyperbaric culture conditions

Abstract Traditional cancer cell lines used as surrogate models in vitro and in vivo have made significant contributions to cancer research and drug discovery. While cell culture and animal studies are critical steps in determining the efficacy, pharmacodynamics, and mechanism of action of novel anti-cancer drugs, it is well-known that cells grown in 2D culture systems have modified growth characteristics and different responses to chemotherapeutic drugs compared to tumors in vivo as a result of differing structural and environmental conditions that fail to replicate in vivo tumor microenvironments. AVATAR bioreactors (Xcell Biosciences, San Francisco, CA) were invented to address these limitations by providing discrete control over oxygen and hyperbaric pressure levels to better mimic the in vivo environment and allow cultured cells to be grown in conditions which mimic the human body. To better serve preclinical research needs, we generated new tumor cell models by long-term acclimating (LTA) existing cancer cells in the AVATAR incubator system using 1% O2 and 2 PSI conditions similar to the conditions expected in the tumor microenvironment (TME). Six different cancer cell lines of diverse origins including pancreas (MIA PaCa-2), breast (BT-474), colon (HCT116), prostate (LNCaP, PC-3) and melanoma (A-375) were adapted for 2-3 months with phenotypic changes recorded. Key marker changes were commonly observed in LTA cells compared to parental lines. For example, in HCT116 colorectal cancer cells, TME culture conditions induced a higher expression level of E-cadherin in both protein and mRNA levels (2.2-fold change), indicating a mesenchymal-epithelial transition of the cell after adaptation. This coincides with the observation that LTA adapted HCT116 cell bodies had a more angular cell morphology as compared to parental cells grown under conventional normoxic culture conditions. In-depth gene-expression analysis using a Nanostring tumor signaling pathway panel identified several common and tissue-specific gene and pathway changes. These included VEGFA, EGF receptor signaling pathway (EGFR, E-Cadherin, GRB7, c-Fos), TGF pathway (IGFBP3, TGFB1, TGFB2, SMAD7), and extracellular matrix signaling (LAMB3, ITGA5, ITGB3, ITGB8, PDGFA, CCND2). Current studies are focusing on drug response testing in 2D and 3D cultures based on above-mentioned gene and signaling pathway changes. Cell proliferation and migration capacity of xenograft LTA cells will be evaluated for the purposes of creating novel murine models for drug screening applications. Citation Format: Yewei Xing, Abriel Czachorowski, James Lim, Scott Wise. Generation of new oncology cell models through long-term acclimation under hypoxic and hyperbaric culture conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6005.

Exploring the Mechanisms of Action of Quercetin for the Treatment of Cervical High-Risk-Human Papilloma Virus Using Network Pharmacology and Molecular Docking

Abstract Objective Our objective was to investigate the therapeutic mechanism of quercetin in the management of cervical HR-HPV through the integration of network pharmacology and molecular docking techniques. Methods The GeneCard database was utilized to analyze and identify potential therapeutic targets in HR-HPV. Subsequently, a protein–protein interaction (PPI) network was constructed by employing the String database. The visualization and construction of PPI networks were accomplished using Cytoscape. The R language was utilized to conduct Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Results A total of 154 active constituents of quercetin were identified through screening. Additionally, 139 target genes associated with the effects of quercetin on cervical HR-HPV were predicted. PPI analyses revealed that threonine kinase Akt1, mitogen-activated protein kinase1, human IL-6 protein, signal transducer and activator of transcription 3, and epidermal growth factor receptor (EGFR) may serve as potential targets for quercetin in the treatment of cervical HR-HPV. Furthermore, GO and KEGG analyses demonstrated that quercetin is involved in various functional pathways, biological processes, molecular categories, including the Th17 signaling pathway, tumor necrotizing factor (TNF) signaling pathway, EGFR signaling pathway, PI3K-Akt signaling pathway, among others. Conclusion Quercetin exhibits multifaceted characteristics, targeting multiple components, pathways, and targets, in the therapeutic intervention of HR-HPV, primarily by modulating inflammatory responses, oxidation reactions, and apoptotic processes.

Synthesis and Biological Evaluation of 3,9-Dioxatetraasteranes as Potential Inhibitors of Epidermal Growth Factor Receptor

Background: Epidermal growth factor receptor (EGFR) is a validated and therapeutically amenable target, and inhibition of the EGFR signaling pathway has emerged as an attractive target for cancer therapy. Methods: The present work was designed to synthesize and evaluate the antiproliferative activity of a novel series of 3,9-dioxatetraasteranes as potential inhibitors of EGFR. All target compounds were evaluated for antiproliferative activity in vitro against A549 and HepG2 cell lines. Results: Among the target compounds, compound B13 displayed the most potent antiproliferative activity against A549 with IC50 = 4.31 μM and HepG2 with IC50 = 6.92 μM. In addition, a molecular docking study was performed to investigate the binding mode and binding capacity with EGFR (PDB code: 1M17). Conclusion: The results indicated that 3,9-dioxatetraasteranes may be promising potential EGFR inhibitors.

Silencing of the PHLDA1 leads to global proteome changes and differentiation pathways of human neuroblastoma cells.

Neuroblastoma (NB) is the most common extracranial pediatric solid tumor originating from the abnormal development of cells of the sympathoadrenal lineage of the neural crest. Targeting GD2 ganglioside (GD2), a glycolipid expressed on neuroblastoma cells, with GD2 ganglioside-recognizing antibodies affects several pivotal signaling routes that drive or influence the malignant phenotype of the cells. Previously performed gene expression profiling helped us to identify the PHLDA1 (pleckstrin homology-like domain family A member 1) gene as the most upregulated gene in the IMR-32 human neuroblastoma cells treated with the mouse 14G2a monoclonal antibody. Mass spectrometry-based proteomic analyses were applied to better characterize a role of PHLDA1 protein in the response of neuroblastoma cells to chimeric ch14.18/CHO antibody. Additionally, global protein expression profile analysis in the IMR-32 cell line with PHLDA1 silencing revealed the increase in biological functions of mitochondria, accompanied by differentiation-like phenotype of the cells. Moreover, mass spectrometry analysis of the proteins co-immunoprecipitated using anti-PHLDA1-specific antibody, selected a group of possible PHLDA1 binding partners. Also, a more detailed analysis suggested that PHLDA1 interacts with the DCAF7/AUTS2 complex, a key component of neuronal differentiation in vitro. Importantly, our results indicate that PHLDA1 silencing enhances the EGF receptor signaling pathway and combinatory treatment of gefitinib and ch14.18/CHO antibodies might be beneficial for neuroblastoma patients. Data are available via ProteomeXchange with the identifier PXD044319.

Network pharmacology analysis and experimental verification of the antitumor effect and molecular mechanism of isocryptomerin on HepG2 cells.

Isocryptomerin (ISO) is a flavonoid isolated from the natural medicine Selaginellae Herba, which has various pharmacological activities. This study investigated the antitumor effect and underlying molecular mechanism of ISO on hepatocellular carcinoma (HCC) HepG2 cells. The cell viability assay revealed that ISO has a considerable killing effect on HCC cell lines. The apoptosis assay showed that ISO induced mitochondria-dependent apoptosis through the Bad/cyto-c/cleaved (cle)-caspase-3/cleaved (cle)-PARP pathway. The network pharmacological analysis found 13 key target genes, and epidermal growth factor receptor (EGFR), AKT, mitogen-activated protein kinase(MAPK), and reactive oxygen species (ROS) signaling pathways were strongly associated with ISO against HCC. Further verification of the results showed that ISO induced apoptosis by increasing p-p38 and p-JNK expression and decreasing p-EGFR, p-SRC, p-ERK, and p-STAT3 expression. Furthermore, ISO induced G0/G1 phase arrest by downregulating p-AKT, Cyclin D, and CDK 4 expression and upregulating p21 and p27 expression in HepG2 cells. Moreover, ISO inhibited HepG2 cell migration by decreasing p-GSK-3β, β-catenin, and N-cadherin expression and increasing E-cadherin expression. Additionally, ISO promoted ROS accumulation in HepG2 cells, and ISO-induced apoptosis, arrest cell cycle, and inhibition of migration were reversed by an ROS scavenger, N-acetyl- l-cysteine. Overall, ISO induced cell apoptosis and cell cycle arrest and inhibited cell migration by ROS-mediated EGFR, AKT, and MAPK signaling pathways in HepG2 cells.

Anticancer Evaluation of Novel Benzofuran-Indole Hybrids as Epidermal Growth Factor Receptor Inhibitors against Non-Small-Cell Lung Cancer Cells.

The epidermal growth factor receptor (EGFR), also known as ErbB1 and HER1, belongs to the receptor tyrosine kinase family. EGFR serves as the primary driver in non-small-cell lung cancer (NSCLC) and is a promising therapeutic target for NSCLC. In this study, we synthesized a novel chemical library based on a benzofuran-indole hybrid scaffold and identified 8aa as a potent and selective EGFR inhibitor. Interestingly, 8aa not only showed selective anticancer effects against NSCLC cell lines, PC9, and A549, but it also showed significant inhibitory effects against the double mutant L858R/T790M EGFR, which frequently occurs in NSCLC. In addition, in PC9 and A549 cells, 8aa potently blocked the EGFR signaling pathway, cell viability, and cell migration. These findings suggest that 8aa, a benzofuran-indole hybrid derivative, is a novel EGFR inhibitor that may be a potential candidate for the treatment of NSCLC patients with EGFR mutations.

Gefitinib enhances healing of long bone fractures in rats via inhibition of the epidermal growth factor receptor signal pathway

Purpose: To investigate the influence of gefitinib on healing of long bone fractures in rats, and the involvement of epidermal growth factor receptor (EGFR) signal route in the process.
 Methods: A model of long bone fracture was established in 30 Sprague-Dawley (SD) rats which were allocated to control and study groups (n = 15/group). Rats in study group received gefitinib (100 mg/kg per day) via gavage, while control rats were given 0.55 % methylcellulose daily for 7 - 42 days. Fracture healing, maximum callus diameter, serum levels of bone markers and mRNA levels of bone turnover indices in the callus, were determined.
 Results: Following 1 week of therapy, fracture lines were clear in both groups, and callus was produced. On days 7, 14, 21, and 28, maximum callus diameter of study group was significantly higher than that of control group (p < 0.05). However, there was no significant difference in the maximum callus diameter between the two groups after 42 days (p > 0.05). On days 7, 14 and 21, there were significantly higher BALP and PINP levels, and TRACP-5b and CTX values in study group than in control (p < 0.05). On days 7 and 14, study group COLa1 mRNA and osteocalcin (OC) mRNA was significantly raised, relative to control values. On days 7, 14 and 21, COL10 mRNA expression was significantly up-regulated in study group relative to controls (p < 0.05). However, mRNA expression levels of COLa1, OC, COL10, and COL2A1 were similar in both groups at other time points.
 Conclusion: Gefitinib enhances the healing of long bone fractures and callus formation in rats, probably through inhibition of EGFR signaling pathway. Therefore, gefitinib is beneficial in bone formation in rats.

VEGF and EGFR signaling pathways are involved in the baicalein attenuation of OVA-induced airway inflammation and airway remodeling in mice

BackgroundAlthough Traditional Chinese Medicine (TCM) has been used for treating asthma for centuries, the understanding of its mechanism of action is still limited. Thus, the purpose of this study was to explore the possible therapeutic effects, and underlying mechanism of baicalein in the treatment of asthma.MethodsFreely availabled atabases (e.g. OMIM, TTD, Genecards, BATMAN-TCM, STITCH 5.0, SEA, SwissTargetPrediction) and software (e.g. Ligplot 2.2.5 and PyMoL) were used for disease drug target prediction and molecular docking by network pharmacology. The efficacy and mechanism of action of baicalein in the treatment of asthma were validated using an ovalbumin (OVA)-induced asthma mouse model and molecular biology techniques.ResultsA total of 1655 asthma-related genes and 161 baicalein-related targets were identified from public databases. Utilizing common databases and software for network pharmacology and molecular docking analysis, seven potential target proteins for the therapeutic effects of baicalein on asthma were selected, including v-akt murine thymoma viral oncogene homolog 1 (AKT1), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein kinase Src (SRC), mitogen-activated protein kinase 3 (MAPK3), matrix metallopeptidase 9 (MMP9), and MAPK1. In vivo, baicalein treatment via intraperitoneal injection at a dose of 50 mg/kg significantly reduced airway inflammation, collagen deposition, smooth muscle thickness, lung interleukin (IL)-4 and IL-13 levels, peripheral blood immunoglobulin (Ig)E levels, as well as the count and ratio of eosinophils in bronchoalveolar lavage fluid (BALF) in an OVA-induced asthma mouse model. Further validation by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting analysis revealed that the VEGF and EGFR signaling pathways involving VEGFA, MAPK1, MAPK3, and EGFR were inhibited by baicalein in the asthma mouse model.ConclusionBaicalein attenuates airway inflammation and airway remodeling through inhibition of VEGF and EGFR signaling pathways in an OVA-induced asthma mouse model. This will provide a new basis for the development of baicalein as a treatment for asthma and highlights the potential of network pharmacology and molecular docking in drug discovery and development.

KBTBD2 promotes proliferation and migration of gastric cancer via activating EGFR signaling pathway

BackgroundTo explore the role of Kelch repeat and BTB (POZ) domain containing 2 (KBTBD2) in Gastric cancer(GC) via studying the level of KBTBD2 and its impact on GC cells and mice model. MethodsExpression of KBTBD2 in GC was analyzed by analysis of TCGA data, Western blotting and Real-time quantitative polymerasechain reaction (RT-qPCR). The role of KBTBD2 on GC cells proliferation, viability, invasion, migration and apoptosis in vitro were assessed by using western blotting，RT-qPCR，CCK-8, EDU, Colony Formation Assay, Wound healing assay, Transwell, JC-1 mitochondrial membrane potential and flow cytometry assay, respectively. And levels of Bcl-2, BAX, PARP, E-cadherin, Vimentin, N-cadherin, EGFR, SOS1, NROS, BRAF,ERK1/2 and GAPDH were tested by western blotting. Relation of KBTBD2 and epidermal growth factor receptor (EGFR) was predicted by KEGG analysis. KBTBD2 gene GSEA enrichment was analyzed by using R language. Moreover, CCK-8, western blotting, and wound healing assays were used to verify the correlation of KBTBD2 and EGFR pathway. Finally, tumor growth in mice was also investigated. Cells proliferation, migration and apoptosis were detected by Ki67 staining, Tunnel staining and mouse lung metastasis model. ResultsKBTBD2 was highly expressed in GC, and was related to poor prognosis. Moreover, silencing KBTBD2 suppressed GC cell proliferation, migration and invasion, while also inhibited the EMT, but promoted apoptosis. At the same time, KBTBD2 overexpression showed opposite results. In addition, KBTBD2 regulated the EGFR pathway. Further, silencing KBTBD2 inhibited tumor growth, cell proliferation and migration but promoted apoptosis in vivo, and KBTBD2 overexpression showed opposite results. ConclusionsKBTBD2 was highly expressed in GC. KBTBD2 promotes the progress of GC by activating EGFR signal pathway. KBTBD2 may thus be a novel target for treating GC.

Interstitial Fluid Shear Stress Induces the Synthetic Phenotype Switching of VSMCs to Release Pro-calcified Extracellular Vesicles via EGFR-MAPK-KLF5 Pathway.

Phenotypic switching (from contractile to synthetic) of vascular smooth muscle cells (VSMCs) is essential in the progression of atherosclerosis. The damaged endothelium in the atherosclerotic artery exposes VSMCs to increased interstitial fluid shear stress (IFSS). However, the precise mechanisms by which increased IFSS influences VSMCs phenotypic switching are unrevealed. Here, we employed advanced numerical simulations to calculate IFSS values accurately based on parameters acquired from patient samples. We then carefully investigated the phenotypic switching and extracellular vesicles (EVs) secretion of VSMCs under various IFSS conditions. By employing a comprehensive set of approaches, we found that VSMCs exhibited synthetic phenotype upon atherosclerotic IFSS. This synthetic phenotype is the upstream regulator for the enhanced secretion of pro-calcified EVs. Mechanistically, as a mechanotransducer, the epidermal growth factor receptor (EGFR) initiates the flow-based mechanical cues to MAPK signaling pathway, facilitating the nuclear accumulation of the transcription factor krüppel-like factor 5 (KLF5). Furthermore, pharmacological inhibiting either EGFR or MAPK signaling pathway blocks the nuclear accumulation of KLF5 and finally results in the maintenance of contractile VSMCs even under increased IFSS stimulation. Collectively, targeting this signaling pathway holds potential as a novel therapeutic strategy to inhibit VSMCs phenotypic switching and mitigate the progression of atherosclerosis.

Dual blockade of EGFR and PI3K signaling pathways offers a therapeutic strategy for glioblastoma

BackgroundGlioblastoma multiforme (GBM) is a devastating disease that lacks effective drugs for targeted therapy. Previously, we found that the third-generation epidermal growth factor receptor (EGFR) inhibitor AZD-9291 persistently blocked the activation of the ERK pathway but had no inhibitory effect on the phosphoinositide 3-kinase (PI3K)/Akt pathway. Given that the PI3K inhibitor GDC-0084 is being evaluated in phase I/II clinical trials of GBM treatment, we hypothesized that combined inhibition of the EGFR/ERK and PI3K/Akt pathways may have a synergistic effect in the treatment of GBM.MethodsThe synergistic effects of cotreatment with AZD-9291 and GDC-0084 were validated using cell viability assays in GBM and primary GBM cell lines. Moreover, the underlying inhibitory mechanisms were assessed through colony formation, EdU proliferation, and cell cycle assays, as well as RNA-seq analyses and western blot. The therapeutic effects of the drug combination on tumor growth and survival were investigated in mice bearing tumors using subcutaneously or intracranially injected LN229 xenografts.ResultsCombined treatment with AZD-9291 and GDC-0084 synergistically inhibited the proliferation and clonogenic survival, as well as induced cell cycle arrest of GBM cells and primary GBM cells, compared to monotherapy. Moreover, AZD-9291 plus GDC-0084 combination therapy significantly inhibited the growth of subcutaneous tumors and orthotopic brain tumor xenografts, thus prolonging the survival of tumor-bearing mice. More importantly, the combination of AZD-9291 and GDC-0084 simultaneously blocked the activation of the EGFR/MEK/ERK and PI3K/AKT/mTOR signaling pathways, thereby exerting significant antitumor activity.ConclusionOur findings demonstrate that the combined blockade of the EGFR/MEK/ERK and PI3K/AKT/mTOR pathways is more effective against GBM than inhibition of each pathway alone, both in vitro and in vivo. Our results suggest that AZD-9291 combined with GDC-0084 may be considered as a potential treatment strategy in future clinical trials.396yfhm1sdcH9_KhVkr-McVideo

EGFR mediates epithelial‑mesenchymal transition through the Akt/GSK-3β/Snail signaling pathway to promote liver cancer proliferation and migration.

Epidermal growth factor receptor (EGFR) is expressed in various types of cancer and is associated with the malignant biological behavior of cancer cells. In the present study, the expression of EGFR in hepatocellular carcinoma (HCC) tissues and liver cancer cells was detected by immunohistochemical staining, western blotting and immunofluorescence. Furthermore, a lentivirus was transduced into HepG2 liver cancer cells to knock down EGFR expression. Cell proliferation and migration, and the expression levels of epithelial-mesenchymal transition (EMT) markers were assessed by EdU staining, Cell Counting Kit-8, colony formation, wound healing and Transwell assays, and western blotting. The results revealed that EGF/EGFR can mediate EMT through the Akt/glycogen synthase kinase-3β (GSK-3β)/Snail signaling pathway to promote HepG2 cell proliferation and migration. Inhibition of the activation of the EGFR signaling pathway can help to partially reverse the EMT phenotype, and inhibit the proliferation and migration of HepG2 cells. In conclusion, the EGFR/Akt/GSK-3β/Snail signaling pathway serves an important role in HCC progression, and inhibition of the activation of the EGFR signaling pathway may be a valuable strategy in liver cancer treatment.

Progress on the EGFR pathway drives targeted therapy for NSCLC

Epidermal growth factor receptor (EGFR) is a key tyrosine kinase receptor that regulates cell survival, proliferation, division, and differentiation. The mutation of the EGFR gene is one of the most common gene mutations responsible for non-small cell lung cancer (NSCLC). Extensive research has been done in the field. Several key EGFR signaling pathways control cell activity, such as MAPK/EPK, PI3K/Akt/mTOR, and JAK/STAT pathways. Mutation of EGFR can cause abnormal activation of signaling cascades, leading to constant cell growth and division, eventually causing tumor growth. Understanding the function of epidermal growth factor receptor and EGFR signaling pathways contributes to the development of targeted treatment for lung cancer. Therefore, through recent research and analysis on the mechanism of action and related pathways of EGFR, this article finds that EGFR tyrosine kinase inhibitor (TKI), a commonly used drug to treat lung cancer, is one of the most effective treatment and it has high potential. However, resistance to TKIs caused by secondary mutations has become a crucial challenge. Novel generations of TKI and combination therapies are needed.

IGF2BP3-EGFR-AKT axis promotes breast cancer MDA-MB-231 cell growth.

Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) is an emerging prognostic indicator, and its elevated expression correlates with malignancy in a broad spectrum of cancers. However, its regulatory networks have not yet been reported. In this study, we identified the regulatory targets of IGF2BP3 in breast cancer MDA-MB-231 cells using RNA immunoprecipitation sequencing (RIP-seq) and high-throughput RNA-sequencing (RNA-seq). We discovered that these targets were enriched in the inflammatory response, endoplasmic reticulum stress, cell cycle, and cancer-related pathways, providing a new perspective for better understanding the functional mechanisms of IGF2BP3. Moreover, we identified that the epidermal growth factor receptor (EGFR), a downstream target, is regulated by IGF2BP3. IGF2BP3 binds to and protects EGFR mRNA from degradation and facilitates cell proliferation via the EGFR/AKT pathway in MDA-MB-231 cells. In addition, IGF2BP3 expression was robust and could not be altered by stimulation with EGF and anti-EGFR siRNA or EGFR signaling pathway inhibitors (gefitinib, LY294002 and SL-327). These results demonstrate that IGF2BP3, as a stubborn oncogene, promotes triple-negative breast cancer MDA-MB-231 cell proliferation by strengthening the role of the EGFR-AKT axis.

The role of polymorphism of the epidermal growth factor gene in the formation of severe manifestations of skin toxicity caused by the use of EGFR inhibitors

Epidermal growth factor receptor (EGFR) inhibitors are widely used to treat various types of cancer, such as non-small cell lung cancer, head and neck cancer, breast cancer, pancreatic cancer, colorectal cancer. During treatment, class-mediated effects such as skin toxicity, interstitial lung disease, hepatotoxicity, ocular toxicity, hypomagnesemia, stomatitis, and diarrhea may occur. The role of epidermal growth factor and its receptors in the vital activity of keratinocytes is key. Dermatological undesirable effects occur in 60–90% of patients, and often persist throughout the entire period of EGFR inhibitor therapy.
 Currently, studies of biomarkers predicting the severity of skin complications of EGFR inhibitor therapy are extremely limited. Thus, it is relevant to study genetic markers reliably associated with the development of severe skin toxicity against the background of EGFR inhibitor therapy, because the EGFR signaling pathway is important for maintaining normal physiological function of the skin. The development of severe skin reactions leads to a reduction in the dose or discontinuation of EGFR inhibitors in the treatment of cancer. Recently, progress has been made in studies of the cutaneous toxicity of EGFR inhibitors.
 Here we briefly describe the mechanism of skin toxicity caused by EGFR inhibitors, current data on the relationship of gene polymorphism and severity of manifestations of undesirable dermatological phenomena.