Overexpression Of Epidermal Growth Factor Receptor Research Articles

Synthesis, ADMET predictions, molecular docking studies, and in-vitro anticancer activity of some benzoxazines against A549 human lung cancer cells.

This study aims to synthesize a series of benzoxazines (1-5) to be examined as an epidermal growth factor receptor (EGFR) inhibitor by in-silico study. The overexpression of EGFR causes the growth of normal lung cells to become uncontrollable, which may lead to cancer formation. We also conducted the absorption, distribution, metabolism, excretions and toxicity (ADMET) properties evaluation and also examined in vitro anticancer assay on human lung cancer cells line, which is A549. Benzoxazines (1-5) were synthesized by reacting anthranilic acid and benzoyl chlorides. The structures of the compounds were determined with 1H, 13C-NMR, HRMS, UV and FT-IR spectrometric methods. Prediction of ADMET was using online pkCSM, and the molecular docking studies were using MVD with EGFR-TKIs as the target (PDB ID: 1M17). In vitro assay of anticancer activity was performed by MTT assay. Compounds 1-5 were successfully synthesized in good yields (71-84%). The ADMET prediction showed that benzoxazines are able to be absorbed through GIT, metabolized by CYP 450, and not hepatotoxic. The title compounds have a greater Moldock Score than Erlotinib, and 3 has the highest activity against A549 compared with other benzoxazines, IC50=36.6μg/mL. Compound (3) more active as anticancer against Human cancer cells line compared with other benzoxazines.

Triple-Negative Metaplastic Breast Carcinoma: Association of Epidermal Growth Factor Receptor Expression With Prognostic Parameters and Clinical Outcome.

IntroductionMetaplastic breast carcinoma (MBC) is one of the rare special subtypes of breast carcinoma associated with poor prognostic features compared with invasive ductal carcinoma. Moreover, therapeutic options are limited in MBC owing to frequent triple-negative profiles of these tumors. Epidermal growth factor receptor (EGFR) is a proto-oncogene that is overexpressed in many human cancers, and is a potential therapeutic target. Therefore, in this study, we evaluated the expression of EGFR in MBC by immunohistochemistry, and its association with clinicopathological and prognostic parameters.MethodsWe conducted a retrospective observational study in the Department of Histopathology at Liaquat National Hospital and Medical College, Pakistan, over a period of seven years. A total of 61 cases with a histopathological diagnosis of MBC were included in the study. All slides were reviewed by histopathologists for diagnostic confirmation. Histopathological parameters, such as tumor size, grade, and nodal metastasis, were recorded. The representative tissue blocks were also retrieved and immunohistochemical studies were performed for cytokeratin 5/6 (CK5/6), Ki67, and EGFR.ResultsThe mean age of the patients was 44.48 ± 13.01 years. The mean tumor size was 5.72 ± 2.72 cm, with most of the cases belonging to tumor (T)-stage T3. Axillary metastasis was present in 57.4% cases, and the perinodal extension was present in 11.5% cases. Most tumors were grade III (85.2%), with a mean Ki67 index of 39.67% ± 20.38%. Most of the cases were nonbasal (83.6%), owing to the absent CK5/6 expression. Tumor recurrence was noted in 14.8% cases, with a median follow-up of 43 (13-83) months and median disease-free survival of 36 (12-60) months. Positive EGFR expression was noted in 52.5% cases. A significant association of EGFR expression was noted with tumor grade, mean Ki67 index, axillary metastasis, and nodal (N)-stage. Cases with positive EGFR expression were found to have higher grade (grade III), with higher Ki67 index, higher frequency of axillary metastasis, and higher N-stage. Moreover, cases with positive EGFR expression had lower disease-free survival compared to cases with negative EGFR expression.ConclusionWe found that a significant proportion of triple-negative MBC expressed EGFR. Moreover, EGFR overexpression was associated with poor pathological parameters and lower disease-free survival. Therefore, EGFR can be considered a potential prognostic biomarker and therapeutic target in triple-negative MBC; however, the correlation between gene amplification and protein overexpression is required to better uncover the role of EGFR as a therapeutic target.

The role of PKA/PP2B-mediated Drp1 phosphorylation and the subsequent EGFR inhibition in Cr(VI)-induced premature senescence

In recent years, frequent hexavalent chromium [Cr(VI)] pollution incidents have severely damaged the ecology and endangered the public health. It is well known that cell senescence could promote the carcinogenesis, thus the related research on the occurrence of premature senescence is of great significance to the elucidation of the carcinogenic mechanism of Cr(VI). We previously confirmed that long-term low-dose Cr(VI) exposure induced premature senescence, but the key molecular events that determine the occurrence of premature senescence are still unclear. In the present study, we found that Cr(VI) induced phosphorylation of dynamin-relatedprotein 1 (Drp1)-S637 site in premature senescent cells, which was accompanied with the decrease of mitochondrial fission. We also demonstrated that the phosphorylation status of Drp1-S637 after Cr(VI) exposure was related to the antagonism of PKA/PP2B, and continuous dephosphorylation of Drp1-S637 attenuated premature senescence caused by Cr(VI). The epidermal growth factor receptor (EGFR) overexpression significantly alleviated the occurrence of premature senescence, and the expressions of EFGR and its downstream molecules were related to the phosphorylation status of Drp1-S637. In brief, we revealed the role of PKA/PP2B-mediated Drp1 phosphorylation and the subsequent EGFR inhibition in Cr(VI)-induced premature senescence. This study is the first time to link the phosphorylation of Drp1 with Cr(VI)-induced premature senescence, in order to find the key molecular events that determine the occurrence of premature senescence and demonstrate the molecular mechanism of abnormal elongated mitochondria formation in the senescence process. The significance of this study is to explore the carcinogenesis of Cr(VI) and provide new ideas and strategies for the targeted treatment of Cr(VI)-related cancers.

Monitoring Receptor Heterodimerization along Intracellular Trafficking Pathways using Anti‐HER2 Therapeutic Antibodies

Overexpression of Human EGF Receptor 2 (HER2) in cancer is a marker of aggressive metastatic disease and poor prognosis. Anti-HER2 monoclonal antibody trastuzumab (TZM) has been successfully used in the clinic over the last decades. However, a large fraction of eligible patients display resistance to this therapy. Deeper investigation of TZM-HER2 binding, internalization and trafficking/degradation in cancer cells may provide some crucial answers. Forster resonance energy transfer Fluorescence lifetime microscopy (FRET-FLIM) offers a unique approach to monitor TZM-HER2 binding via the reduction of donor fluorophore lifetime. Thus, FRET-FLIM provides an efficient method to quantify ligand-receptor binding and internalization in cancer cells with the additional benefit of sensing intracellular microenvironment heterogeneity such as modulation of endocytic trafficking upon drug treatment. In this study, we report quantification of binding of NIR-labeled therapeutic antibodies FRET pairs to their respective receptors, e.g. HER2 and/or HER1, in AU565 breast cancer cells in various combinations, i.e. anti-HER1 cetuximab donor – cetuximab acceptor vs. cetuximab donor - TZM acceptor, to assess the dynamics of HER receptor homo and heterodimerization behavior. We also monitor FRET FLIM events along the intracellular trafficking of these anti-HER2 and anti-HER1 probes. Our data indicate that in the presence of TZM, HER1 as well as HER3 receptors localization is shifted towards plasma membrane. Furthermore, the distribution pattern of fluorescence lifetime during endocytic trafficking differs when comparing “homo” vs “hetero FRET” pairs. These results suggest that HER2 dimerization pattern can switch towards hetero- and oligomerization during TZM treatment which may result in modulation of oncogenic signaling. In parallel, Western blotting and immunofluorescent analysis of AU565 cells strongly indicate that 24h TZM treatment substantially upregulate HER3 and pHER2 levels both in 2D and 3D (spheroids) models. Together, these data imply that in cultured breast cancer models, short-term TZM treatment may inadvertently increase oncogenic fitness probably as a result of adaptation to HER2 - TZM binding.

EGFR Overexpression and Sequence Analysis of KRAS, BRAF, and EGFR Mutation Hot Spots in Canine Intestinal Adenocarcinoma.

Epidermal growth factor receptor (EGFR) is overexpressed in many human colorectal cancers and anti-EGFR agents are employed as immunotherapies. However, KRAS, EGFR, and BRAF gene mutations can influence the activity of the anti-EGFR agents. We evaluated EGFR expression at protein and mRNA levels in canine intestinal adenocarcinomas using immunohistochemistry (IHC) and RNA in situ hybridization (RNA-ISH). We also investigated the mutation status of EGFR, KRAS, and BRAF to aid the development of anti-EGFR agents for canine intestinal adenocarcinoma. EGFR expression was highest in adenocarcinoma, followed by intramucosal neoplasia (adenoma and in situ carcinoma), and nonneoplastic canine intestinal tissue, at both protein (P = .000) and mRNA (P = .005) levels. The EGFR, KRAS, and BRAF genes showed wild-type sequences at the mutation hot spots in all 13 specimens. Thus, EGFR might serve as a promising diagnostic marker in canine intestinal adenocarcinoma, and further studies would be needed to develop EGFR-targeted anticancer therapies.

MiR-338-5p Inhibits EGF-Induced EMT in Pancreatic Cancer Cells by Targeting EGFR/ERK Signaling.

The epidermal growth factor (EGF) pathway plays critical roles during cancer cell epithelial-mesenchymal transition (EMT) process and metastasis. Epidermal growth factor receptor (EGFR), as one of the important receptors of EGF, undergoes autophosphorylation with the stimulation of EGF and activates MAPK/ERK, PI3K/Akt/mTOR, and other pathways. Here, we identified EGFR was a target of miR-338-5p. Upon EGF treatment, overexpression of miR-338-5p not only downregulated EGFR expression and inhibited MAPK/ERK signaling, but also inhibited EMT and metastasis process of pancreatic cancer (PC) cells. In the clinical pathological analysis, miR-338-5p was significantly down-regulated in 44 pairs PC tissues and its expression was negatively associated with lymph node metastasis and AJCC stage. Furthermore, Overexpression of EGFR partially reversed the protective effect of miR-338-5p overexpression on EGF-mediated migration and invasion in PC cells. Taken together, miR-338-5p controls EGF-mediated EMT and metastasis in PC cells by targeting EGFR/ERK pathways. Here, we hope to provide new insights into the molecular mechanisms of pancreatic cancer, and may help facilitating development of EGFR-based therapies for human cancer.

Evaluation of effect of epidermal growth factor receptor and vascular endothelial growth factor overexpression in survival of patients with glioblastoma multiforme

Background. In the central nervous system, glioblastoma multiforme (GBM) is one of the most important neoplasms in adults. Amplification of EGFR and VEGF genes is common in GBM. However, the role of overexpression of EGFR and VEGF in survival of patients with GBM has been a contentious issue. Therefore, we performed the present study to assess the survival rate of patients with EGFR and VEGF overexpression. Materials and methods. Resected samples of GBM patients were evaluated by immunohistochemistry for overexpression of VEGF and EGFR. The patients were followed up for a year. Results. The mean±sd of age of patients was 56.2±13.1 years. The majority of the patients were male (65.9%). Most of the patients had primary GBM (67%), notwithstanding 33% of the patients with secondary GBM. Moreover, 19.2% and 49.5% of the samples were VEGF-positive and EGFR-positive, respectively. Overall 6, 12-, and 18-month survival rates were shown to be 61.5±5.1%, 17.6±4%, and 4.4±2.1%, respectively. There was a significant difference between the mean±se survival rate in VEGF-negative patients (12±1.9 months) VEGF-positive patients (7.8±0.5 months) (P=0.045). Conclusions. We found an association between VEGF and EGFR over-expression and the survival rate of GBM patients. The VEGF overexpression was significantly associated with the overall survival rate of the GBM patients, but failed to have a prognostic value for their mortality rate. However, EGFR was a predictor of overall survival rate and mortality of GBM patients. Moreover, VEGF overexertion has a stronger association with survival rate in GBM, compared to EGFR overexpression.

Bio Functional Evaluation of EGFR Expression as a Prognostic Indicator in Oral Squamous Cell Carcinoma and a Recommendation for Personalized Targeted Therapy with Anti EGFR Inhibitors

Background: Carcinoma is a complex, multifactorial and a devastating disease. Understanding the molecularchanges that leads to disease enables one to develop strategies to prevent, provide an early diagnosis andserve as targets for therapy. Epidermal Growth Factor Receptor (EGFR), a 170-kDa cell-surface proteinis a tyrosine kinase receptor from the ErbB family and is involved in many biological processes thataffect tumour development, growth progression, differentiation, inhibition of apoptosis and developmentof metastasis. Methods: Study included 54 cases of oral squamous cell carcinomas. EGFR expression byimmunohistochemistry has been studied, correlated with clinical parameters, known prognostic factors andpatient survival to note its significance.Conclusion: Head and Neck Squamous Cell Carcinoma (HNSCC) with or without regional lymph nodemetastases, are challenging to treat effectively. The prognosis for the patients with advanced stage of thedisease still remains poor. The correlation of EGFR overexpression with tumour size, grade, stage andsurvival suggests that EGFR expression can be considered as having prognostic significance and is apotential target for therapy with EGFR inhibitors in HNSCC. Further studies are required to assure theviability of EGFR levels in saliva as non-invasive prognostic marker and also as an indicator of recurrence.

Preclinical Evaluation of the Association of the Cyclin-Dependent Kinase 4/6 Inhibitor, Ribociclib, and Cetuximab in Squamous Cell Carcinoma of the Head and Neck.

Simple SummaryWe previously showed that ribociclib induces cell cycle arrest in some human papillomavirus (HPV)-negative squamous cell carcinomas of the head and neck (SCCHN) models. However, in vivo, ribociclib has only a cytostatic effect, suggesting that its activity needs to be optimized in combination with other treatments. We investigated the activity of ribociclib in combination with cetuximab in several HPV-negative SCCHN patient-derived tumor xenograft (PDTX) models. We found that the combination of cetuximab and ribociclib was not significantly more active than cetuximab monotherapy. In addition, our observations also suggest that the combination of cetuximab with a cyclin-dependent kinase (CDK) 4/6 inhibitor may reduce the activity of the CDK4/6 inhibitor in some cetuximab-resistant models. Our work has significant clinical implications since combinations of anti-epidermal growth factor receptor (EGFR) therapy and CDK4/6 inhibitors are currently being investigated in clinical trials.Epidermal growth factor receptor (EGFR) overexpression is observed in 90% of human papillomavirus (HPV)-negative squamous cell carcinomas of the head and neck (SCCHN). Cell cycle pathway impairments resulting in cyclin-dependent kinase (CDK) 4 and 6 activation, are frequently observed in SCCHN. We investigated the efficacy of ribociclib, a CDK4/6 inhibitor, in combination with cetuximab, a monoclonal antibody targeting the EGFR, in HPV-negative SCCHN patient-derived tumor xenograft (PDTX) models. The combination of cetuximab and ribociclib was not significantly more active than cetuximab monotherapy in all models investigated. In addition, the combination of cetuximab and ribociclib was less active than ribociclib monotherapy in the cetuximab-resistant PDTX models. In these models, a significant downregulation of the retinoblastoma (Rb) protein was observed in cetuximab-treated mice. We also observed Rb downregulation in the SCCHN cell lines chronically exposed and resistant to cetuximab. In addition, Rb downregulation induced interleukin 6 (Il-6) secretion and the Janus kinase family member/signal transducer and activator of transcription (JAK/STAT) pathway activation that might be implicated in the cetuximab resistance of these cell lines. To conclude, cetuximab is not an appropriate partner for ribociclib in cetuximab-resistant SCCHN models. Our work has significant clinical implications since the combination of anti-EGFR therapy with CDK4/6 inhibitors is currently being investigated in clinical trials.

Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin With or Without Panitumumab in Patients With Advanced Urothelial Carcinoma: Multicenter, Randomized, French Unicancer GETUG/AFU 19 Study

Epidermal growth factor receptor (EGFR) overexpression is frequent and associated with poor outcome in urothelial carcinoma. EGFR inhibition could improve the antitumor activity of chemotherapy. Patients with advanced, treatment-naïve, histologically confirmed advanced urothelial carcinoma and no HRAS or KRAS mutation in the primary tumor received dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) without or with the anti-EGFR monoclonal antibody panitumumab (Pmab). A randomized (1:2) phase II design was used with progression-free survival (PFS) as the primary endpoint. Ninety-seven eligible patients were randomized; 96 patients were evaluable for toxicity and 87 for efficacy. The median PFS were 6.8 months (95% confidence interval [CI], 6.3-9.2) for dd-MVAC and 5.7 months (95% CI, 4.6-6.4 months) for dd-MVAC+Pmab. For both immunohistochemical and molecular definition of basal/squamous-like (BASQ) tumors, no difference was observed in objective response rates or PFS between the two arms in BASQ and non-BASQ tumors. dd-MVAC+Pmab was associated with more serious adverse events and no improvement in efficacy outcomes.

CALM1 promotes progression and dampens chemosensitivity to EGFR inhibitor in esophageal squamous cell carcinoma

BackgroundCalmodulin1 (CALM1) has been identified as one of the overexpression genes in a variety of cancers and EGFR inhibitor have been widely used in clinical treatment but it is unknown whether CALM1 and epidermal growth factor receptor (EGFR) have a synergistic effect in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to explore the synergistic effects of knock-out CALM1 combined with EGFR inhibitor (Afatinib) and to elucidate the role of CALM1 in sensitizing the resistance to Afatinib in ESCC.MethodImmunohistochemistry (IHC) and qRT-PCR were used to examine the expression of CALM1 and EGFR in ESCC tissues. Kaplan–Meier survival analysis was used to analyze the clinical and prognostic significance of CALM1 and EGFR expression in ESCC. Furthermore, to evaluate the biological function of CALM1 in ESCC, the latest gene editing technique CRISPR/Cas9(Clustered regularly interspaced short palindromic repeats)was applied to knockout CALM1 in ESCC cell lines KYSE150, Eca109 and TE-1. MTT, flow cytometry, Transwell migration, scratch wound-healing and colony formation assays were performed to assay the combined effect of knock-out CALM1 and EGFR inhibitor on ESCC cell proliferation and migration. In addition, nude mice xenograft model was used to observe the synergistic inhibition of knock-out CALM1 and Afatinib.ResultsBoth CALM1 and EGFR were found to be significantly over-expressed in ESCC compared with paired normal control. Over-expressed CALM1 and EGFR were significantly associated with clinical stage, T classification and poor overall prognosis, respectively. In vitro, the combined effect of knock-out CALM1 mediated by the lentivirus and EGFR inhibitor was shown to be capable of inhibiting the proliferation, inducing cell cycle arrest at G1/S stage and increasing apoptosis of KYSE-150 and Eca109 cells; invasion and migration were also suppressed. In vivo, the results of tumor weight and total fluorescence were markedly reduced compared with the sgCtrl-infected group and sgCAML1 group.ConclusionOur data demonstrated that knock-out of CALM1 could sensitize ESCC cells to EGFR inhibitor, and it may exert oncogenic role via promotion of EMT. Taken together, CALM1 may be a tempting target to overcome Afatinib resistance.

Immune Stimulating Antibody-Photosensitizer Conjugates via Fc-Mediated Dendritic Cell Phagocytosis and Phototriggered Immunogenic Cell Death for KRAS-Mutated Pancreatic Cancer Treatment.

Although cetuximab (CTX) is a chimeric epidermal growth factor receptor (EGFR) antibody, the antitumor efficacy of CTX has a negligible effect in patients with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutated pancreatic adenocarcinoma. Given that all extant treatments are ineffective due to the undruggable characteristics of KRAS-mutated cancer, alternative strategies have been investigated. In this work, CTX-conjugated maleimide-polyethylene glycol-chlorin e6 (CMPC) is designed to strengthen its antitumor efficacy. With strong affinity for EGFR overexpressing Aspc-1 cells, CMPC with laser exerts the greatest cytotoxicity (90%) and induction of immunogenic cell death. Through a combination of fragment crystallizable region-mediated antigen uptake by CTX and danger-associated molecular patterns released by photodynamic therapy (PDT), phagocytosis and maturation of dendritic cells treated with CMPC plus laser show dramatic increases. In vivo biodistribution and antitumor effect also demonstrate that CMPC has significant tumor selectivity and tumor ablation efficacy upon laser irradiation. Furthermore, a large number of CD4+ , CD8+ T cells and mature DCs and natural killer cells are infiltrated in CMPC with laser-treated tumor tissues and tumor-draining lymph nodes, revealing both innate and adaptive cellular immune stimulation. This synergistic effect with CMPC and laser treatment provides an effective approach for pancreatic cancer immunotherapy attributed to both CTX and PDT.

Expression of Estrogen and Progesterone Receptors in Papillary Thyroid Carcinoma in Korea.

PurposeThe aim of this study was to examine the rate of expression of estrogen receptor α (ERα) and β1 (ERβ1), progesterone receptor (PR), and rate of overexpression of epidermal growth factor receptor (EGFR) in a relatively large cohort of patients with papillary thyroid carcinoma (PTC). We also aimed to examine whether each receptor influenced clinicopathological characteristics and prognosis of PTC.Materials and MethodsWe made a microarray of paraffin-embedded PTC surgical tissues from 436 patients. We compared the results of the immunohistochemical staining for each hormone receptor with clinicopathological characteristics.ResultsThe positive expression rate of hormonal receptors was 40.4% for ERα, 83.7% for ERβ1, and 71.3% for PR in patients with PTC. Overexpression of EGFR was shown in 19.3% of patients with PTC. The age was lower (44.6±12.1 years vs. 47.1±12.5 years, p=0.040) and tumor smaller (0.96±0.69 cm vs. 1.13±0.82 cm, p=0.020) in the ERα positive group, which also showed higher PR positivity (80.7% vs. 65.0%, p < 0.001) and overexpression of EGFR (27.3% vs. 13.8%, p < 0.001). However, neither the positivity of hormone receptors nor overexpression of EGFR affected the recurrence of PTC.ConclusionIn conclusion, most (94.6%) patients with PTC were found to exhibit positive expression for ERs or PR. We also found that neither the positive expression of hormone receptors nor overexpression of EGFR were associated with the recurrence of PTC.

Mitogen-activated protein kinase inhibition-induced modulation of epidermal growth factor receptor signaling in human head and neck squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) overexpression is one of the most notable characteristics in head and neck squamous cell carcinoma (HNSCC). The MAPK kinase (MEK) inhibitor trametinib has shown efficacy to treat HNSCC; however, the molecular mechanism remains unclear. HNSCC lines, mouse models, Western blot, and flow cytometry were employed to analyze the anticancer effects of trametinib. The JHU-011, JHU-022, and JHU-029 HNSCC cells with different genetic alterations were highly susceptible to trametinib. Trametinib effectively reduced EGFR expression, which was accompanied by the reduction of pro-survival protein MYC, and the increased expression of a MYC-targeted cyclin-dependent kinase inhibitor p27kip1 and pro-apoptotic protein BIM. Trametinib resulted in G1 arrest of the cells, markedly reduced cell numbers in S phase, and significantly increased apoptosis. In mouse models, trametinib strongly inhibited tumors growth. The MAPK-ERK signaling inhibition by trametinib may target EGFR and the downstream proteins against HNSCC.

Synergistic therapeutic benefit by combining the antibody drug conjugate, depatux-m with temozolomide in pre-clinical models of glioblastoma with overexpression of EGFR.

Depatux-m is an antibody drug conjugate (ADC) that targets and inhibits growth of cancer cells overexpressing the epidermal growth factor receptor (EGFR) or the 2-7 deletion mutant (EGFRvIII) in tumor models in vitro and in vivo. Treatment of patients suffering from relapsed/refractory glioblastoma (GBM) with a combination of depatux-m and temozolomide (TMZ) tended to increase overall survival. As a first step to understand the nature of the interaction between the two drugs, we investigated whether the interaction was synergistic, additive or antagonistic. The efficacy of ADCs, antibodies, TMZ and radiation was tested in xenograft models of GBM, U-87MG and U-87MG EGFRvIII. Both models express EGFR. U-87MG EGFRvIII was transduced to express EGFRvIII. Changes in tumor volume, biomarkers of cell death and apoptosis after treatment were used to measure efficacy of the various treatments. Synergism of depatux-m and TMZ was verified in three-dimensional cultures of U-87MG and U-87MG EGFRvIII by the method of Chou and Talalay. Combined with TMZ and radiotherapy (RT), depatux-m inhibited xenograft growth of U-87MG and U-87MG EGFRvIII more than either treatment with depatux-m or TMZ + RT. Durability of the response to depatux-m + TMZ + RT or depatux-m + TMZ was more pronounced in U-87MG EGFRvIII than in U-87MG. Efficacy of depatux-m + TMZ was synergistic in U-87MG EGFRvIII and additive in U-87MG. Adding depatux-m enhances the efficacy of standard of care therapy in preclinical models of GBM. Durability of response to depatux-m + TMZ in vivo and synergy of the drug-drug interaction correlates with the amount of antigen expressed by the tumor cells.

Correlation between the overexpression of epidermal growth factor receptor and pathological features of gastric cancer: a meta-analysis.

BackgroundTo evaluate the overexpression of epidermal growth factor receptor (EGFR) and its correlation with pathological features of gastric cancer, so as to provide a theoretical basis for anti-EGFR targeted therapy.MethodsPubMed, Embase, Web of Science, CNKI, Wanfang were used to retrieve literature on EGFR expression and gastric cancer tissues between January 2009 and March 2020 and Stata 15.0 software was used to analyze. Age, gender, degree of differentiation, depth of invasion, lymph node metastasis, distant metastasis and TNM staging were analyzed with odds ratio (OR) and 95% confidence interval (CI).ResultsA total of 17 articles were included, with 4,424 patients with gastric cancer, of which 1,268 patients with EGFR overexpression. EGFR was related to the infiltration depth (OR =3.26, 95% CI: 1.95–5.44); related to lymph node metastasis (OR =2.10, 95% CI: 1.45–3.04); related to distant metastasis (OR =1.96, 95% CI: 1.41–2.72); related to TNM staging (OR =3.98, 95% CI: 2.09–7.59). However, EGFR overexpression is not concerned with age, gender and differentiation.ConclusionsEGFR overexpression has the predictive value for depth of invasion, lymph node metastasis, TNM staging and distant metastasis of gastric cancer, and may be a predictor of adverse prognosis of gastric cancer. Targeted therapy for EGFR may be considered as one of the means of comprehensive treatment for gastric cancer.

Epidermal growth factor receptor promotes tumor progression and contributes to gemcitabine resistance in osteosarcoma

Osteosarcoma (OS) is the most common type of primary malignant tumors that originate in the bone. Resistance to chemotherapy confers a poor prognosis on OS patients. Dysregulation of the epidermal growth factor receptor (EGFR) signaling has been reported in sarcomas. However, the functional contribution of EGFR hyperactivation to the tumor biology and chemoresistance remains largely unexplored in OS. In this study, we aimed to investigate the role of EGFR in OS progression and in the response of OS to gemcitabine treatment. The EGFR expression was found to be upregulated in fibroblastic OS cell lines. EGFR knockdown suppressed OS cell proliferation, migration, and invasion in vitro and tumor formation in vivo. Conversely, EGFR overexpression promoted the growth and motility of OS cells. In terms of mechanism, the levels of phospho-Akt and phospho-ERK were decreased upon EGFR knockdown but increased as a result of EGFR overexpression, implying a possible involvement of PI3K/Akt and ERK pathways in mediating the effects of EGFR on OS cells. Moreover, the level of phospho-EGFR was increased in OS cells when exposed to gemcitabine treatment. A more profound proliferative inhibition and a higher rate of apoptosis were obtained in OS cells via inducing cell cycle arrest at G1 phase upon gemcitabine treatment combined with EGFR knockdown, as compared to gemcitabine alone. On the contrary, EGFR overexpression counteracted the growth-inhibiting and pro-apoptotic effects of gemcitabine in OS cells. The present study suggests that EGFR promotes tumor progression and contributes to gemcitabine resistance in OS.

Computational Evaluation of Bioactive Compounds from Colocasia affinis Schott as a Novel EGFR Inhibitor for Cancer Treatment.

Introduction:Epidermal growth factor receptor (EGFR) is a transmembrane protein that belongs to the ErbB/HER-family of tyrosine kinase receptors. Somatic mutations and overexpression of EGFR have been reported to play a vital role in cancer cell development and progression, including cell proliferation, differentiation, angiogenesis, apoptosis, and metastatic spread. Hence, EGFR is an important therapeutic target for the treatment of various types of epithelial cancers. Somatic mutations have led to resistance to clinically approved synthetic EGFR inhibitors. Furthermore, synthetic EGFR inhibitors have been associated with several side effects. Thus, there is a need to develop novel EGFR inhibitors with an acceptable biosafety profile and high efficacy.Methods:Herein, we employed structural bioinformatics and theoretical chemistry techniques via molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) calculation, density functional theory analysis (DFT), and pharmacokinetic study to identify novel EGFR inhibitors.Results:The stringent molecular docking and MM-GBSA calculations identified MET 793, LYS 745, PHE 723, ASP 855, ARG 411, and THR 854 as principal amino acid residues for EGFR-ligands interactions. Furthermore, Colocasia affinis Schott compounds exhibited higher binding energy and more stable interactions than the reference compound (gefitinib). DFT analysis also ascertains better bioactivity and chemical reactivity of C. affinis Schott with favorable intramolecular charge transfer between electron-donor and electron acceptor groups. The pharmacokinetic profile of C. affinis Schott bioactive compounds satisfies Lipinski’s rule of five assessment.Conclusion:Collectively, C. affinis Schott compounds demonstrated higher inhibitory potentials against EGFR and better pharmacological properties when compared with gefitinib. C. affinis Schott compounds are therefore suggested as promising therapeutic EGFR inhibitors for cancer treatment.

Immunoexpression of TTF1 and p63 Differentiates Lung Adenocarcinomas in Sputum Samples.

Context:Differentiating NSCLC as either adeno or squamous type and identification of Epidermal Growth Factor Receptor (EGFR) mutations is clinically relevant for lung cancer patients for selecting treatment. Thyroid transcription factor-1 (TTF-1) and p63 were demonstrated as useful markers for histologic typing of lung cancer. Mutation and overexpression of EGFR has been reported in a subset of non-small cell lung cancers. If these markers can be validated for the differential diagnosis of adenocarcinoma in a sputum sample itself, it will be highly beneficial for lung cancer patients.Aims:To evaluate whether immunocytochemical expression of TTF-1, p63, and EGFR proteins in sputum samples can be used for differential diagnosis of lung adenocarcinoma by comparing with that of the corresponding tissue samples.Settings and Design:Ninety sputum samples and matched tissue samples were used for the study.Subjects and Methods:Monolayered smears and cell blocks of sputum and the corresponding tissue samples were immunostained with the standard ABC method. The expression patterns of these markers were analyzed statistically and compared with clinic-pathological parameters.Statistical Analysis Used:Chi-square test and paired t-test.Results:The p63 protein had a positive expression in 73.9% of SCC whereas TTF1 had positive expression in 75.8% of ADC. The EGFR expression was positive in 27 cases of adenocarcinoma, 21 cases of SCC and 19 cases of NSCLC.Conclusions:Immunocytochemistry of the aforementioned antibodies in sputum samples can be used as supplementary evidence for the subtyping of NSCLC.

EGFR signaling promotes resistance to CHK1 inhibitor prexasertib in triple negative breast cancer.

Aim: Innate resistance to the CHK1 inhibitor prexasertib has been described, but resistance mechanisms are not understood. We aimed to determine the role epidermal growth factor receptor (EGFR) plays in innate resistance to prexasertib in triple negative breast cancer (TNBC).Methods: Using a panel of pre-clinical TNBC cell lines, we measured the sensitivity to prexasertib. We examined the effect activation of EGFR had on prexasertib sensitivity. We measured the synergy of dual blockade of EGFR with erlotinib and CHK1 with prexasertib in TNBC cell lines and xenografts.Results: EGFR overexpression and activation increased resistance to CHK1 inhibition by prexasertib. EGFR promoted the phosphorylation of BCL2-associated agonist of cell death (BAD), inactivating its pro-apoptotic functions. Inhibition of EGFR reversed BAD phosphorylation, increasing sensitivity to prexasertib.Conclusion: The use of prexasertib as a monotherapy in TNBC has been limited due to modest clinical responses. We demonstrated that EGFR activation contributes to innate resistance to prexasertib in TNBC and potentially other cancers. EGFR expression status should be considered in clinical trials examining prexasertib’s use as a monotherapy or combination therapy.