Epidermal Growth Factor Receptor Research Articles

Bioinformatics analysis of the potential receptor and therapeutic drugs for Alzheimer's disease with comorbid Parkinson's disease.

Now, there are no sensitive biomarkers for improving Alzheimer's disease (AD) and comorbid Parkinson's disease (PD). The aim of the present study was to analyze differentially expressed genes (DEGs) in brain tissue from AD and PD patients via bioinformatics analysis, as well as to explore precise diagnostic and therapeutic targets for AD and comorbid PD. GFE122063 and GSE7621 data sets from GEO in NCBI, were used to screen differentially expressed genes (DEGs) for AD and PD, and identify the intersected genes, respectively. Intersected genes were analyzed by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then, STRING site and Cytoscape were used to construct a protein-protein interaction (PPI) network, CytoNCA algorithm to analyze and evaluate centrality, Mcode plug-in to analyze module, and Cytohubba to screen key genes. Combined GO-KEGG enrichment analysis with Cytoscape algorithm to screen the key gene in AD complicated with PD. Then, the DEGs for AD and PD were imported into the Association Map (CMap) online platform to screen out the top 10 small molecule drugs, and using molecular docking techniques to evaluate the interactions between small molecule drugs and key genes receptors. In total, 231 upregulated genes and 300 downregulated genes were identified. GO analysis revealed that the DEGs were highly enriched in signal transduction, and KEGG analysis revealed that the DEGs were associated with the MAPK and PI3K-Akt signaling pathways. Epidermal growth factor receptor (EGFR) was identified as a potential receptor gene in AD and comorbid PD. EGFR was upregulated in both AD and PD, and the proteins that interact with EGFR were enriched in the Ras/Raf/MAPK and PI3K/Akt signaling pathways. Semagacestat was identified as a drug with therapeutic potential for treating AD complicated with PD. There was a high binding affinity between semagacestat and EGFRNTD, with seven hydrogen bonds and one hydrophobic bond. Semagacestat may improve the health of patients with AD complicated with PD through the regulation of the Ras/Raf/MAPK and PI3K/Akt signaling pathways by EGFR, providing evidence supporting the structural modification of semagacestat to develop a more effective drug for treating AD complicated with PD.

Gallocin-derived Engineered Peptides Targeting EGFR and VEGFR in Colorectal Cancer: A Bioinformatic Approach.

Colorectal cancer (CRC) treatment using time-saving and cost-effective targeted therapies with high selectivity and low toxicity drugs, is a great challenge. In primary investigations on Gallocin, as a most proposed factor in CRC pathogenesis caused by Streptococcus gallolyticus, it was surprisingly found that this bacteriocin has four α-helix structures and some anti- cancer sequences. The aim of this study was to determine the ability of Gallocin-based anticancer peptides (ACPs) against epidermal growth factor receptor (EGFR) and vascular epidermal growth factor receptor (VEGFR) and the evaluation of their pharmacokinetics properties using bioinformatics approaches. Support vector machine algorithm web-based tools were used for predicting ACPs. The physicochemical characteristics and the potential of anti-cancer activity of Gallocin-derived ACPs were determined by in silico tools. The 3D structure of predicted ACPs was modeled using modeling tools. The interactions between predicted ACPs and targets were investigated by molecular docking exercises. Then, the stability of ligand-receptor interactions was determined by molecular dynamic simulation. Finally, ADMET analysis was carried out to check the pharmacokinetic properties and toxicity of ACP. Four amino acid sequences with anti-cancer potential were selected. Through molecular docking, Pep2, and Pep3 gained the best scores, more binding affinity, and strong attachments by the formation of reasonable H-bonds with both EGFR and VEGFR. Molecular simulation confirmed the stability of Pep3- EGFR. According to pharmacokinetic analysis, the ACPs were safe and truthful. Designed peptides can be nominated as drugs for CRC treatment. However, different in-vitro and in-vivo assessments are required to approve this claim.

Custom-Designed Probes for the Accurate Determination of Epidermal Growth Factor Receptor Mutations and Their Allelic Configuration.

The identification of single nucleotide polymorphisms (SNPs) is of paramount importance for disease diagnosis and clinical prognostication. In the context of nonsmall cell lung cancer (NSCLC), the emergence of resistance mutations, exemplified by the epidermal growth factor receptor (EGFR) T790 M and C797S, is intricately linked to the therapeutic efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Herein, a highly efficient and specific SNP detection platform for T790 M and C797S mutations has been engineered through the integration of an asymmetric polymerase chain reaction (PCR) and an ingeniously tailored four-way junction (4WJ) probe. Notably, a molecular beacon (MB) probe was judiciously designed to discern the allelic configuration of these mutations. The administration of first- and third-generation EGFR-TKIs demonstrates therapeutic efficacy solely when the mutations are in the trans configuration, characterized by a low fluorescence signal. In contrast, significant fluorescence by the MB probe is indicative of the C797S mutation being in a cis arrangement with T790M, thereby rendering the cells refractory to the therapeutic interventions of both first- and third-generation EGFR-TKIs. The assay is capable of concurrently detecting two point-mutations and ascertaining their allelic positions in a single test within 1.5 h, enhancing both efficiency and simplicity. It also exhibits high accuracy in the identification of clinical samples, offering promising implications for therapeutic guidelines. By enabling tailored treatment plans based on specific genetic profiles, our approach not only advances the precision of NSCLC treatment strategies but also marks a significant contribution to personalized medicine.

A bibliometric and visualization analysis of research trends and hotspots on targeted therapy for breast cancer from 2003 to 2022.

Breast cancer is a significant public health issue, exhibiting the most pronounced occurrence and fatality rates among malignant neoplasms globally. Targeted therapy is a medical intervention that focuses on specific molecular markers. This study aims to investigate and evaluate the current research trends and directions in the field of targeted therapy for breast cancer using bibliometric analysis. The Web of Science database was utilized to retrieve relevant articles published between 2003 and 2022. The VOSviewer software and Bibliometrix package in the R language were employed to conduct co-occurrence and clustering analyses of authors, countries, institutions, journals, references, and the CiteSpace tool was utilized for keyword burst detection. A total of 2,258 articles were included and the annual number of publications increased rapidly. The most prolific country on this topic was the USA (n=898, 39.77%) and the University of Texas MD Anderson Cancer Center published most papers (n=93). Dennis J. Slamon and Gabriel N. Hortobagyi stood out in the field, with Dennis J. Slamon leading in terms of co-citations(n=653) and Gabriel N. Hortobagyi topping the list in terms of published articles(n=18). The most productive journal was Breast Cancer Research and Treatment and the most cited journal was Journal of Clinical Oncology. The clustering of keywords indicated that the primary focus of researches in the past two decades was on the development and clinical evaluation of tumor-targeted drugs associated with the epidermal growth factor receptor (EGFR) family signaling pathway, and explored mechanisms related to biological behavior of breast cancer. Keywords co-occurrence and burst analysis identified current research hotspots and potential research trends. This study employed bibliometric analysis to examine research on targeted therapy for breast cancer over a span of 20 years, and identified development trends of research and elucidated potential research trajectories in the domain of this topic. This study helps in the identification of prospective collaborators and partner institutions for researchers.

Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy ± 1 Year of Everolimus in Patients With High-Risk, Hormone Receptor-Positive, Early-Stage Breast Cancer.

Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy. Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC. One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%). One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

Cisplatin Monotherapy as a Treatment Option for Patients with HER-2 Negative Breast Cancer Experiencing Hepatic Visceral Crisis or Impending Visceral Crisis.

Hepatic visceral crisis (VC), characterized by a rapid total bilirubin increase with disease progression, poses a life-threatening risk in advanced breast cancer (ABC). International consensus guidelines define VC and touch on impending VC (IVC). Limited data exist on systemic treatments for hepatic VC/IVC. This study explores the safety and efficacy of cisplatin monotherapy in patients with Human Epidermal Growth Factor Receptor 2- negative breast cancer (BC) and hepatic IVC/VC. In this retrospective single-center cohort study data of patients treated with cisplatin monotherapy (60-80mg/m2, every 3-4weeks) between 2016 and 2023 at a reference Cancer Centre in Southern Poland were analyzed. 33 female patients (24/33 hormonal-positive) with the mean age 53.84years were included. Participants progressed on median 2 prior palliative systemic treatment lines. In 10/23 patients hepatic VC and in 23/33 IVC (rapid, symptomatic liver progression; extensive liver involvement; alanine or aspartate aminotransferase > 2 × normal limit; significant increases in lactate dehydrogenase, alkaline phosphatase, or gamma-glutamyl transferase) were identified. Median progression-free survival was 1.87months and median overall survival 2.67months. 33% of the patients presented stable disease or partial response. Eight patients experienced adverse events grade ≥ 3: in five the dose of cisplatin was reduced; two stopped the treatment. Due to the hepatotoxicity of BC-active drugs, specific recommendations for systemic treatment are scarce. Our study explored cisplatin's potential use, finding it to be a viable option in patients with performance status 0 or 1 experiencing hepatic IVC/VC, irrespective of liver function parameters and other factors.

Phase II Efficacy and Safety of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer (BLOSSOM).

Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs. In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6. A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set-T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2. The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.

Impact of PD-L1 Expression on the Overall Survival of Caucasian Patients with Advanced EGFR-Mutant NSCLC Treated with Frontline Osimertinib.

The treatment of advanced non-small cell lung cancer (NSCLC) harboring an oncogenic epidermal growth factor receptor mutation (EGFRm) is currently based on osimertinib, a third-generation tyrosine kinase inhibitor (TKI). High Programmed death ligand 1 (PD-L1) expression ≥ 50% demonstrated to be a negative prognostic factor, mostly among Asian populations treated with 1st/2nd generation TKI. We investigated the impact of PD-L1 expression on the progression free survival (PFS) and overall survival (OS) within a cohort of patients receiving osimertinib as first-line treatment. Our bi-centre French retrospective study included all newly diagnosed patients with an advanced EGFRm (common and uncommon) NSCLC, between May 2018 and November 2022, treated with osimertinib. The primary endpoint was OS according to tumor proportion score PD-L1 expression (low/intermediate < 50% vs high ≥ 50%). Survival analyses were performed using Kaplan-Meier method and Cox model for adjusted multivariate analysis. Of 96 patients, median age was 71 (IQR 62-76), 70 were women (72.9%), 81 had a performance status (PS) 0-1 (84.3%). Median follow-up was 22.6 months (95% CI 20.5-24.7). Twenty patients (20.8%) had high PD-L1 expression ≥ 50%. No significant differences in baseline characteristics were observed based on PD-L1 status. Patients with PD-L1 ≥ 50% had significant shorter PFS and OS than those with PD-L1 < 50%, respectively 9.3 vs 17.5 months (p = 0.044 months) and 14.3 vs 26.0 months (p = 0.025). Multivariable adjustment for baseline characteristics found that PS ≥ 2 (HR 2.79, 95% CI 1.12-6.93, p = 0.027), PD-L1 ≥ 50% (HR 2.61, 95% CI 1.31 to 5.22, p = 0.007) and uncommon EGFR mutation (HR 4.59, 95% CI 1.95-10.80, p = <0.001) were associated with a shorter OS. Brain metastases at diagnosis and age ≥ 65 were not, respectively HR 1.66 (95% CI 0.90-3.06, p = 0.11) and HR 0.95 (95% CI 0.50-1.80, p=0.9). Our study found that PD-L1 expression ≥ 50% was associated with a shorter OS in EGFRm NSCLC patients treated with first line osimertinib. Further research is warranted to understand the underlying molecular and cellular mechanisms of this correlation.

Retrospective registry of patients with locally advanced/metastatic HR+/HER2- breast cancer treated in clinical practice in Andalusia.

Limited data are available regarding the real-world effectiveness and safety of Cyclin Dependent Kinase 4/6 inhibitor (CDK4/6i) (palbociclib/ribociclib) just as a first-line treatment for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2‒) metastatic breast cancer (MBC). To assess whether clinical or demographic characteristics limit access to first-line CDK4/6i treatment in clinical practice in the Autonomous Community of Andalusia (Spain) between November 2017 and April 2020. In addition, effectiveness will be described in an exploratory analysis. Physicians from 12 centers participated in selecting demographic and clinical characteristics, treatment, and outcome data from women with HR + /HER2- MBC treated with or without CDK4/6i in addition to hormonal in the first-line setting, in a 3:1 proportion. Kaplan-Meier analysis estimated progression-free rates (PFRs) and survival rates (SRs). A total of 212 patients were included, of whom 175 (82.5%) were in the CDK4/6i treatment group and 37 (17.5%) were in the non-CDK4/6i treatment group (control group). Patients in the CDK 4/6i treatment group were younger (p = 0.0011), the biopsies of the metastatic site at the moment of the relapse were most commonly performed (p = 0.0454), and had multiple metastatic sites (p = 0.0025). The clinical benefit rate (CBR) was 82.3% in the CDK4/6i group and 67.8% in the control group. Median time to a progression event or death (PFS) was 20.4months (95%CI 15.6-28) in the CDK4/6i group and 12.1months (95%CI 7.9-not reached) in the control group. Younger patients, biopsies of metastatic disease and with multiple metastatic sites were more frequently treated with CDK4/6i in our daily clinical practice.

Epidemiology, risk factors and molecular subtypes of Breast Carcinoma

Breast cancer (BC) is the leading cause of cancer-related death among women and the most commonly diagnosed cancer worldwide. The 5-year overall survival (OS) from BC has increased steadily in most of the developed countries. The incidence rates of BC vary worldwide, with high rates in North America, Northern and Western Europe, intermediate rates in South America and Southern Europe, and low rates in Africa and Asia. In Egypt, BC represents about 37.7% of total cancer cases among women. Gene amplification is a frequent device leading to the overexpression of oncogenes in human cancers. At present, the prognosis, classification, and treatment of BC are dependent on tumor histological grading, tumor stage, as well as 3 major protein markers: Estrogen receptor (ER), Progesterone receptor (PR) and Human epidermal growth factor receptor type 2 (HER2). Despite the efforts to improve the effectiveness of the combination of surgical approach, radio-chemotherapy, endocrine-therapy, and human epidermal growth factor receptor-2 (HER-2)-based targeted therapy, there is an immense clinical need for new therapeutic strategies and molecular targets.

Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC.

Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR-tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC. In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review. A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P = 0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged. Treatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.).

Validation of the AJCC 8th Edition Breast Cancer Prognostic Staging System in Legacy Alliance Trials (AFT-01).

The 8th edition American Joint Committee on Cancer staging system combined anatomic stage (AS) with receptor status and grade to create prognostic stage (PS). PS has been validated in single-institution and cancer registry studies; however, missing human epidermal growth factor receptor 2 (HER2) status and variable treatment and follow-up create limitations. Our objective was to compare the relative prognostic ability of PS versus AS to predict survival using breast cancer clinical trial data. Women with non-metastatic breast cancer enrolled in six Alliance for Clinical Trials in Oncology trials were included (enrollment years 1997-2010). AS and PS were constructed using pathological tumor size, nodal status, estrogen receptor (ER), progesterone receptor (PR), HER2 status, and grade. Unadjusted Cox proportional hazard models were estimated to predict overall survival within 5 years, with AS and PS as predictor variables. The relative predictive power of staging models was assessed by comparing Harrell concordance indices (C-indices). Kaplan-Meier-based mortality estimates were compared by stage. Overall, 6924 women were included (median age 53years); 45.2% were diagnosed with ER+/PR+/HER2- tumors, 26.2% with HER2+ tumors, and 17.1% with ER-/PR-/HER2- tumors. Median follow-up time was 5 years (interquartile range 2.95-5.00). PS significantly improved predictive performance (C-index 0.721) for overall survival compared with AS (0.700) (p=0.020). Kaplan-Meier hazard estimates suggested PS did not distinguish mortality risk between patients with IIB and IIIA or IB and IIA disease. PS has significantly improved predictive performance for OS compared with AS. As systemic therapies evolve, it will be important to re-evaluate the prognostic staging system, particularly for patients with intermediate-stage cancers. gov Identifier: NCT02171078.

EGFR mutation testing trends for patients with metastatic, non-squamous non-small cell lung cancer (non-SQ NSCLC) in Queensland, Australia from 2014-2021.

e13505 Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Epidermal growth factor receptor (EGFR) is the most common actionable mutation in non-small cell lung cancer (NSCLC) with routine testing recommended globally. In late 2013, screening for EGFR mutations was publicly funded in Australia for metastatic non-SQ-NSCLC. However, timely EGFR results are not universally available, often limited by tissue quantity/quality or prolonged turnaround times. This in turn affects access to treatment and thus survival. Methods: We aimed to examine the rates of EGFR testing over time and explore factors impacting results. Cases were identified from the Queensland Oncology Repository, a clinical database consolidating diagnostic, treatment and outcome data for all Queenslanders with cancer through the Queensland Cancer Registry. Cases were included if they had metastatic non-SQ-NSCLC, EGFR testing available via Pathology Queensland, and no other metastatic solid organ cancer within 1 year. Primary outcomes were EGFR mutation testing rates and time from first biopsy to EGFR mutation result, stratified by year of diagnosis and rurality. Results: A total of 3369 cases were included, of which 2871 had EGFR testing. The EGFR mutant (mt) rate was 12.6%, while 16.1% of cases had no EGFR results. Of cases without a conclusive EGFR result, reasons included: 179 transitioned to best supportive care before testing, 208 with insufficient tissue for a conclusive result, and 155 without testing for unclear reasons. The average time from biopsy to EGFR result improved from 29.9 days in 2014 to 21.5 days in 2021, with no significant difference in time to result between major cities, regional or remote areas. Cases with no EGFR results were more prevalent in rural areas. The proportion of patients living in outer regional/remote areas with no EGFR result was 21.1% compared to 15.5% in those living in major cities/inner regional sites. This was a relative increase of 36.2% (95% CI: 10.1% - 68.6%), a significant result (χ2 = 7.7483, p=0.005). Cases with no EGFR results in outer regional and remote sites declined from 30.1% in 2014-2015 to 15.3% in 2020-2021. Conclusions: EGFR mutation testing and result time has improved since 2014. Though time to result was not affected by rurality, significantly more rural patients lacked conclusive EGFR data, highlighting a gap in access to care. The cumulative EGFR no result rate of 16% and result time of 24 days indicates health systems need to more rapidly adapt to new treatment paradigms, particularly in the era of targeted therapies. [Table: see text]

Identification of a patient tissue-based phosphorylation site as a biomarker for epidermal growth factor receptor (EGFR) activity in non-small cell lung cancer.

3143 Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths globally. EGFR tyrosine kinase inhibitors (TKIs) have shown promise in treating NSCLC, yet resistance to these agents is common and current biomarkers rely on genetic data alone. Therefore, identifying reliable biomarkers to more comprehensively monitor EGFR activity and predict therapeutic responses is paramount. Here, we report an uncharacterized threonine phosphorylation site within core regulator of the EGFR pathway SHP2, that is strongly predictive of EGFR activity as defined by genetic mutation status that shows potential as a clinically relevant biomarker. Methods: Using DIA mass spectrometry phosphoproteomics, we could quantify &gt;20,000 phosphosites from patient normal adjacent tumor (NAT) and primary tumor tissue. We further characterized these tissues using whole genome sequencing allowing us to define the mutational status of the EGFR. Statistical analysis was undertaken across all phospho-sites that identified a single uncharacterized phospho-site as a strong predictor of EGFR kinase activity. Finally, we generated monoclonal antibodies against the phospho-peptide and tested these in patient FFPE primary tumor tissue using immunohistochemistry to correlate phosphorylation levels with EGFR activation status. Results: Our results highlight how an individual phosphosite on SHP2 closely correlates with EGFR activity as defined by genetic mutation status in patient tissue. Interestingly, we further identify a group of patients who carry wild type EGFR yet have a phospho-signal potentially indicative of high EGFR activation without genetic aberration. These results were corroborated by a phospho-site specific antibody in FFPE tissue IHC, with strong signals observed in patients with an activating EGFR mutation (n=5), and complete absence of signal in patients harboring a wild type EGFR and no detectable mass spec signal (n=5). Conclusions: Our findings suggest that this uncharacterised SHP2 phosphosite may serve as a potent biomarker for EGFR activity in NSCLC. Further validation of the monoclonal antibodies as tools for this clinically relevant biomarker is required in larger patient cohorts to elucidate the role of the phosphosite in therapy response. This novel biomarker has the potential to guide therapeutic decision-making and contribute to personalized medicine strategies for NSCLC patients.

Phase 1 study of BDTX-1535, an oral 4th generation covalent EGFR inhibitor, in patients with recurrent glioblastoma: Preliminary dose escalation results.

2068 Background: Epidermal growth factor receptor ( EGFR) gene is the most frequently altered oncogenic driver in glioblastoma (GBM). In-frame deletion alterations (e.g., EGFRvIII) and missense mutations co-occur in the setting of EGFR gene amplification and are characterized as a hallmark of disease pathogenesis in GBM. BDTX-1535 is an oral, highly potent, brain penetrant, selective, irreversible 4th generation tyrosine kinase inhibitor that targets EGFR alterations in GBM and NSCLC. Preliminary results of the Phase 1 dose escalation study (NCT05256290) of patients with recurrent GBM (rGBM) are presented here. Methods: BDTX-1535-101 is a first-in-human study that enrolled patients with either rGBM harboring EGFR alterations following standard of care or patients with locally advanced or metastatic EGFR mutated NSCLC that progressed on prior EGFR TKIs. Using an adaptive Bayesian optimal interval design in the Phase 1 part, patients were enrolled at increasing dose cohorts and were treated daily for 21-day cycles until treatment discontinuation. The primary objective was to determine the BDTX-1535 recommended Phase 2 dose based on the overall safety, PK, pharmacodynamics, and preliminary antitumor activity. Results: Twenty-seven patients with rGBM were enrolled in the Phase 1 cohort that consisted of 54 patients in total including 27 patients with NSCLC. Patients were treated across seven dose levels (15mg – 400mg QD). The mean age of patients with rGBM was 58.7 years (range 41-85) with 96% of patients with previous temozolomide (TMZ) treatment and a median of 2 lines of prior therapy (range 1-4). The most common all-grade treatment-related AEs across all cohorts were rash (78%), diarrhea (41%), fatigue (15%), stomatitis (11%), decreased appetite (11%), nausea (11%) and paronychia (11%). Gr 3 TRAEs ≥ 10% included rash (19%) reported at 300 or 400 mg QD doses. Plasma exposure of BDTX-1535 increased dose proportionally and had a half-life of ~15h, supporting once daily dosing. The maximum tolerated dose (MTD) is 300 mg QD. Among 19 evaluable patients for response based on RANO criteria, 1 confirmed partial response was observed and 8 patients achieved stable disease. Five patients remained on BDTX-1535 with stable disease for an extended period (&gt;5 months) who previously performed poorly on TMZ with short treatment duration, and 1 patient continues on BDTX-1535 after 16 months of treatment. Conclusions: BDTX-1535 was well-tolerated up to 300mg daily, which is the MTD, and promising preliminary clinical activity was observed in patients with rGBM after relapse on standard of care treatment. Given the inability to reconfirm EGFR status at the time of treatment with BDTX-1535 in this Phase 1 trial, further exploration of BDTX-1535 in a “window of opportunity” study is ongoing (NCT06072586). Clinical trial information: NCT05256290 .

Molecular Docking, Molecular Dynamics Simulation, and Analysis of EGFR-derived Peptides against the EGF

Background: The epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase receptor family known as ErbB. The EGFR signaling pathway is an important regulator of cell proliferation, differentiation, division, and survival, as well as cancer development in humans. Epidermal growth factor, betacellulin, amphiregulin, transforming growth factor and heparin-binding EGF-like growth factor are high-affinity ligands of EGFR. Objective: Tumor progression can be effectively prevented by inhibiting EGF/EGFR interactions. In this study, many anti-EGF peptides targeting EGFR binding regions were designed, modeled, and evaluated. After selecting the peptides with the highest binding energy to the EGF, the interactions between the candidate peptides and all of the key EGFR ligands were investigated. Methods: To identify an EGF-binding peptide capable of blocking EGFR-EGF interactions, large-scale peptide mutation screening was performed. Using the AntiCP server, several possible peptides with anticancer properties were identified. The ClusPro analysis was performed in order to analyze the interactions between EGF and all of the library peptides. A total of five peptides with favorable docking scores were identified. The stability of three peptides with the best docking scores in complex with EGF was verified, applying molecular dynamics simulation with the help of the GROMACS software package. Finally, the interaction of candidate peptides with transforming growth factor-alpha, heparin-binding EGF-like growth factor, and betacellulin was investigated using the ClusPro server. Results: After the screening of modeled peptides by the ClusPro server and GROMACS software, two anti-EGF peptides of Pep4 and Pep5 with 31 residues were developed. Then, we demonstrate that both of these peptides can bind to the other high-affinity ligands of EGFR and block TGFA/EGFR, HBEGF/EGFR, and BTC/EGFR interactions. Conclusion: The findings suggest novel insights for developing therapies based on peptides for inhibiting the EGF, TGFA, HBEGF, and BTC signaling cascade in cancer cells. Pep4 and Pep5 designed in this work, are recommended as potentially promising anticancer peptides for further experimental evaluation.

DFT, Molecular Docking, Bioactivity and ADME Analyses of Vic-dioxim Ligand Containing Hydrazone Group and its Zn(II) Complex.

Cancer is one of the diseases affecting a large population worldwide and resulting in death. Finding new anti-cancer drugs that are target-focused and have low toxicity is of great importance. This study aimed to investigate the effects of vic-dioxime derivatives carrying hydrazone group and its Zn(II) complex on cancer using molecular docking, bioactivity and quantum chemical calculations. Molecular docking studies were performed on epidermal growth factor receptor and vascular endothelial growth factor receptor 2 target proteins. Furthermore, molecular geometry was performed, and the frontier molecular orbitals, Mulliken charges and molecular electron density distribution were evaluated using density functional theory. Also, the bioactivity parameters of the compounds were evaluated, and ADME analysis was performed using web-based tools. Higher binding affinity was observed for Zn(II) complex with target proteins vascular endothelial growth factor receptor 2 and against epidermal growth factor receptor when compared with LH2. Only the Zn(II) complex against the epidermal growth factor receptor had ligand efficiency and fit quality in the valid range. Furthermore, LH2 has the most potent electrophilic ability (acceptor) among other compounds. Moreover, both LH2 and Zn(II) complexes strongly satisfy Lipinski's rule of five. In conclusion, these novel compounds, especially Zn(II) complex, can be new candidates for anticancer drug development studies which are target-focused and have low toxicity.

Synergistic Effects of Neratinib in Combination With Palbociclib or Miransertib in Brain Cancer Cells.

Aberrant expression and activation of epidermal growth factor receptor (EGFR) resulted in approval of several forms of EGFR inhibitors in the treatment of patients with a wide range of epithelial cancers. However, no EGFR inhibitor has yet been approved for the treatment of patients with brain cancer, indicating that targeting EGFR alone may not be sufficient in some patients. In this study, we investigated the role of all members of the EGFR family, other growth factor receptors, cell-cycle proteins, and downstream cell signaling pathways (e.g., mitogen-activated protein kinase (MAPK), serine/threonine protein kinase (AKT), signal transducer and activator of transcription (STAT3), Src, Abelson murine leukemia viral oncogene homolog (Abl)) on the growth of a panel of human brain cancer cell lines (HBCCLs). We examined the growth response of HBCCLs to treatment with 17 targeted agents compared to two cytotoxic drugs. Of the targeted agents, the irreversible pan-human epidermal growth factor receptor (HER) inhibitors neratinib and afatinib were more effective than erlotinib and lapatinib at inhibiting the growth of all HBCCLs, and the cyclin-dependent kinase (CDK)1/2/5/9 inhibitor dinaciclib was the most potent targeted agent. We found that treatment with Src/Abl/c-kit inhibitor dasatinib, signal transducer and activator of transcription (STAT3) inhibitor stattic, Abl/platelet-derived growth factor receptor (PDGFR)α/vascular endothelial growth factor (VEGFR)2/fibroblast growth factor receptor (FGFR)1 inhibitor ponatinib, and the tropomyosin receptor kinase (TRK)/ROS proto-oncogene 1 receptor tyrosine kinase (ROS)/anaplastic lymphoma kinase (ALK) inhibitor entrectinib, also inhibited the growth of all HBCCLs. Interestingly, these agents were more effective in inhibiting growth of HBCCLs when proliferating at a slower rate. In addition to inhibiting the proliferation of HBCCLs, treatment with neratinib, dinaciclib, dasatinib, stattic and trametinib inhibited the migration of brain tumor cell line A172. Notably, we found that treatment with neratinib in combination with palbociclib (CDK4/6 inhibitor), or miransertib (AKT1/2/3 inhibitor) resulted in synergistic growth inhibition of all HBCCLs. Our results support that repurposing drugs like neratinib in combination with the palbociclib or miransertib may be of therapeutic potential in brain cancer and warrants further investigations.

A Visual Analysis of the Research Dynamics in Resistance to EGFR Inhibitors for NSCLC

A Visual Analysis of the Research Dynamics in Resistance to EGFR Inhibitors for NSCLC

Preclinical development of ATR04-484, an auxotrophic strain of Staphylococcus epidermidis, for the topical treatment of epidermal growth factor receptor (EGFR) inhibitor-induced dermal toxicity.

e24074 Background: Agents targeting the EGFR-mediated signaling pathway are commonly used for the treatment of advanced lung, pancreatic, colorectal, and head and neck cancers. Significant dermal toxicities, which occur in up to 90% of patients treated with EGFR inhibitors (EGFRis) and other therapies inhibiting downstream signaling pathways, may be disruptive to a patient’s quality of life and adherence to therapy. Inhibition of the EGFR pathway may suppress host defenses and lead to opportunistic pathogenic colonization or infection. EGFRi-induced dermal toxicity is associated with elevated levels of Staphylococcus aureus and IL-36γ. ATR04-484 is a topical ointment containing S. epidermidis strain SE484, isolated from a healthy human volunteer that was selected for its ability to inhibit S. aureus and IL-36γ . Methods: Reconstructed human epidermis (RHE) and ex vivo pig skin were used to measure the effect of ATR04-484 on S. aureus in therapeutic and prophylactic settings with S. aureus added prior to or after ATR04-484, respectively. To evaluate the anti-inflammatory effects of ATR04-484, IL-36γ levels were measured on untreated RHE and RHE treated with erlotinib alone or in combination with ATR04-484. 104 colony-forming units (CFU) of methicillin-resistant (MRSA) or methicillin-sensitive (MSSA) S. aureus were used. Toxicology was assessed by measuring cell viability in three in vitro toxicology assays: the eye irritant potential was tested on 3D reconstituted human cornea-like epithelium (RhCE), the skin irritant potential of the strain in the ointment was assessed on 3D RHE, and the skin corrosive potential was evaluated on RHE. Results: ATR04-484 comparably inhibited growth of both MRSA and MSSA in therapeutic and prophylactic settings. In a therapeutic setting, ATR04-484 inhibited MRSA growth by 1 log (90%) compared to untreated MRSA in both RHE and pig skin. In a prophylactic setting, ATR04-484 inhibited MRSA growth by approximately 5 logs on RHE and 2 logs on pig skin. Additionally, application of ATR04-484 reduced IL-36γ to a level comparable to untreated RHE. The effect was dose-dependent; application of 109CFU/cm2 of ATR04-484 showed more potent IL-36γ reduction compared to 108 CFU/cm2. The three toxicology assays indicate that ATR04-484 does not cause irritation or corrosion. Conclusions: In these preclinical studies, ATR-04-484 showed a promising preclinical profile for the treatment of EGFRi-induced dermal toxicity by significantly reducing S. aureus growth, completely ameliorating IL-36γ levels, and showing no safety concerns.