Search Results (1,572)

Background/Objectives: Colorectal cancer (CRC) is molecularly heterogeneous, and the KRAS (Kirsten rat sarcoma viral oncogene homolog) genotype both governs eligibility for anti-EGFR (epidermal growth factor receptor) therapy and carries prognostic weight. Central Asian data are scarce: no Kazakhstani series has described the KRAS variant spectrum, linked it to survival, or reported mutation detection rates across specimen types and PCR platforms. Methods: We studied 332 patients with morphologically confirmed stage II–IV colorectal adenocarcinoma. KRAS status was determined in formalin-fixed paraffin-embedded (FFPE) tumor tissue by allele-specific real-time PCR (RT-PCR) covering six selected codon 12 and 13 variants. Overall survival (OS) was estimated by the Kaplan–Meier method for the whole cohort and with stage stratification. Separately, mutation detection rates were recorded in three non-overlapping groups of different patients: plasma RT-PCR on the Idylla platform (n = 30), plasma nanoplate digital PCR (dPCR) on QIAcuity One (n = 120), and a routine tissue RT-PCR series (546 evaluable of 550). Because these groups differed in patients, specimen type, and mutation panel, this comparison describes observed detection rates only and supports no inference about analytical sensitivity, specificity, or concordance. Results: KRAS was mutated in 149/332 tumors (44.9%); codon 12 supplied 80.5% of variants, led by G12D (32.2%), G12V (24.8%) and G13D (19.5%). Median OS did not differ between mutant and wild-type tumors (39.0 vs. 36.6 months; p = 0.40). Variant-level differences were directionally consistent, but none was significant, and all were exploratory and unadjusted for multiplicity. Observed detection rates were 40.3% for tissue RT-PCR (220/546), 13.3% for plasma RT-PCR (4/30; continuity-corrected p = 0.006 vs. tissue), and 50.8% for plasma dPCR (61/120; continuity-corrected p = 0.044, Pearson p = 0.034 vs. tissue). BRAF V600E was detected by plasma dPCR in 11/120 cases (9.1%). Conclusions: This first Kazakhstani series places KRAS frequency within the internationally reported range and shows that variant-level reporting reveals prognostic structure that a binary call conceals. The higher detection rate seen with plasma dPCR is hypothesis-generating, not evidence of platform superiority, and motivates a prospective paired-sample study with harmonized mutation panels. Full article

Diabetic painful neuropathy (DPN) is a common complication of diabetes. Despite ongoing efforts, the underlying biological mechanisms of DPN remain poorly understood. Hyperglycemia-mediated oxidative stress can affect cell barrier properties, triggering low-grade inflammation. Previous studies have reported increased histone deacetylase (HDAC) activity and altered expression of tight junction proteins in diabetes, which may link to nerve damage. This study examined the effects of the HDAC inhibitor FK228 on cell barrier-mediated changes in the spinal cord and dorsal root ganglia (DRG) of type 2 diabetic mice. Diabetic mice were treated with FK228 (1 mg/kg, twice a week for 3 weeks). Behavioral assessment of cold hypersensitivity was assessed at the end of the treatment regimen. In vitro studies were conducted using ND7/23 immortalized DRG cells. The expression of tight junction proteins (occludin, claudin-1, and zona occludens-1 or ZO-1) and a number of stress-related cellular markers, including HDAC2, growth-associated protein (GAP) 43, epidermal growth factor receptor (EGFR), and nuclear factor erythroid 2-related factor (Nrf2), were evaluated in DRG, spinal cord tissue, and cultured ND7/23 DRG cells following treatment. FK228 treatment demonstrated changes in cold pain sensitivity as well as the expression of tight junction proteins and stress related markers in both in vivo and in vitro models of diabetic neuropathy. These findings indicate that HDAC inhibition by FK228 may support the maintenance of tight junction protein expression and alter cellular stress responses in the spinal cord and DRG, suggesting a possible role of FK228 in mitigating DPN. Full article

The epidermal growth factor receptor (EGFR) was the first receptor tyrosine kinase identified soon after v-Src was recognized as a tyrosine kinase. EGFR signaling begins when EGF binds to EGFR at the cell surface, inducing receptor dimerization, activation, and autophosphorylation. The resulting phosphotyrosine sites recruit downstream effectors that activate signaling cascades such as the RAS-RAF-MEK-ERK and PI3K-Akt pathways, thereby regulating cell growth, proliferation, and survival. EGF binding also promotes EGFR endocytosis, which can direct the receptor to lysosomal degradation. Aberrant EGFR activity is associated with many cancers, and the receptor has been therapeutically targeted using small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Furthermore, EGFR endocytosis has been exploited for the targeted delivery of anticancer agents into EGFR-expressing cancer cells through antibody–drug conjugates (ADCs) and antibody–nanoparticle conjugates (ANCs). Although ADCs and ANCs both utilize mAbs as homing mechanisms to recognize cancer-associated antigens, they further harness EGFR endocytosis to deliver therapeutic payloads directly into target cells. In this review, we briefly discuss EGFR structure, activation, signaling, and endocytosis, as well as the mechanisms underlying EGFR function in cancer development. We then focus on current advances and future perspectives in using EGFR endocytosis pathways to improve targeted cancer drug delivery and therapy, particularly in the context of ANCs. Full article

Background: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a major challenge in the treatment of EGFR-mutant lung adenocarcinoma. Identifying biomarkers associated with resistance may improve understanding of the underlying molecular mechanisms. Objective: This study aimed to identify candidate biomarkers associated with EGFR-TKI resistance using integrated bioinformatics analysis and RT-qPCR validation. Methods: Two Gene Expression Omnibus (GEO) datasets (GSE123066 and GSE178755) were analysed to identify differentially expressed genes (DEGs). Overlapping DEGs were subjected to protein–protein interaction (PPI) network construction, Gene Ontology (GO), KEGG pathway enrichment, and Kaplan–Meier survival analyses. Selected candidate genes were subsequently validated by RT-qPCR in an independent clinical cohort. Results: A total of 76 overlapping DEGs were identified, including 52 upregulated genes enriched in cell proliferation, hypoxia response, EGFR signalling, and metabolic processes. KEGG analysis identified the PI3K–Akt signalling pathway as significantly enriched. Kaplan–Meier analysis showed that higher expression of TGFA, DDIT4, and SOX9 was associated with shorter progression-free survival. RT-qPCR validation demonstrated significantly increased SOX9 expression in the resistant group, whereas TGFA and DDIT4 showed no statistically significant differences. Conclusions: Integrated bioinformatics analysis identified TGFA, DDIT4, and SOX9 as candidate genes associated with EGFR-TKI resistance in EGFR-mutant lung adenocarcinoma. These findings provide a basis for further investigation of resistance-associated biomarkers, although larger independent cohorts and functional studies are required before clinical application. Full article

Epidermal growth factor receptor (EGFR)-targeted therapy represents one of the earliest and most established examples of precision oncology in non-small-cell lung cancer (NSCLC), with more than 10 approved agents, including tyrosine kinase inhibitors, bispecific antibodies and antibody–drug conjugates. Over the past two decades, the diagnostic and therapeutic landscape of EGFR-mutant NSCLC has evolved from empiric treatment to mutation subtype-guided strategies, from advanced disease to earlier-stage interventions, and from monotherapy to rational combination regimens. Somatic EGFR mutations remain key predictive biomarkers guiding treatment selection, therapeutic intensification, resistance mechanism-directed treatment, and disease monitoring through plasma circulating tumor DNA burden. In parallel, germline EGFR alterations are increasingly recognized as contributors to inherited lung cancer susceptibility, particularly among never-smokers and familial clusters. Germline EGFR T790M is the best-characterized pathogenic variant, creating a permissive background for multifocal lung nodules and lung adenocarcinoma development, often following acquisition of a second somatic EGFR driver mutation. Recent familial, regional, and paired tumor–normal sequencing studies have expanded the evidence beyond isolated case reports and support an emerging hereditary lung cancer predisposition phenotype. Clinically, germline EGFR should be suspected when EGFR T790M is detected prior to TKI exposure, particularly at variant allele fractions near 50%, or in patients with multifocal ground-glass nodules, multiple primary lung adenocarcinomas, early-onset disease, never/light smoking history, or family history of lung cancer. Confirmation requires germline testing and genetic counseling. This review highlights the current knowledge, recent advances, and future directions in somatic and germline EGFR-mutant NSCLC, emphasizing translational relevance for clinicians and researchers. Full article

The discovery of activating epidermal growth factor receptor (EGFR) mutations transformed the management of non-small cell lung cancer and has driven two decades of therapeutic advances in precision oncology across metastatic, resectable, and unresectable locally advanced disease, including central nervous system (CNS) control. Consequently, treatment outcomes for patients with tumors harboring classical EGFR mutations have markedly improved. Despite these advances, many questions remain unanswered, and the expanding number of treatment options has created new challenges in treatment selection and sequencing. This narrative review summarizes contemporary data on the management of classical EGFR-mutant NSCLC, encompassing novel therapeutic approaches across disease stages, biomarker-informed resistance strategies, multimodality treatment integrating radiotherapy, CNS-directed management, and challenging scenarios such as small-cell transformation. We also discuss emerging fourth-generation inhibitors, nucleic-acid delivery platforms, and data-enabled personalized treatment. We highlight evolving standards of care, unresolved knowledge gaps, and research priorities for the next decade. Full article

Epidermal growth factor receptor (EGFR) mutations drive hepatocellular carcinoma (HCC) progression, and the T790M gatekeeper substitution is the predominant mechanism of acquired resistance to EGFR-targeted therapies. Herein, we present multiscale quantum-classical in silico predictions of Phyllanthus niruri phytochemicals as non-covalent EGFR T790M binders, employing molecular docking, 100 ns molecular dynamics, MM-PBSA/MM-GBSA, per-residue decomposition, PCA/LDA, DFT at B3LYP-D3(BJ)/def2-TZVP, and comparative wild-type EGFR simulations. Five phytochemicals exhibited computationally predicted binding affinities against EGFR T790M exceeding the non-covalent binding component of osimertinib (−25.74 kcal/mol): corilagin (−53.71 ± 5.05 kcal/mol), eriodictyol-7-rhamnopyranoside (−44.35 ± 4.51 kcal/mol), isoquercetin (−44.23 ± 2.92 kcal/mol), rutin (−42.15 ± 4.50 kcal/mol), and kaempferol-4-rhamnoside (−41.68 ± 3.69 kcal/mol). Wild-type EGFR simulations (PDB 1M17) yielded a selectivity index (IS) of 2.76 for corilagin (<!-- MathType@Translator@5@5@MathML2 (no namespace).tdl@MathML 2.0 (no namespace)@ --> Full article

Most cancers are fatal and remain challenging to cure due to changes in tumorigenesis and therapeutic resistance. Despite significant advancements in cancer therapy, a substantial proportion of malignancies exhibit resistance to conventional therapies, driven primarily by cancer plasticity and the emergence of multidrug resistance. Recent cancer treatments include cytotoxic chemotherapy, molecular targeted therapy, and immune checkpoint inhibitors. A major hallmark of cancer cells is their ability to develop sophisticated evasion mechanisms that bypass programmed cell death when exposed to anti-cancer drugs. In addition, malignant cells evade the efficacy of anti-cancer drugs by altering cell proliferation, survival, and metastasis. To suppress oncogenic characteristics, necroptosis-based therapies have attracted substantial attention, as they can inhibit tumorigenesis and improve treatment outcomes across many cancer types. Furthermore, an increasing body of research focuses on suppressing tumorigenesis by targeting receptors that are overexpressed in cancer cells. In this review, we elucidate how tumorigenesis is inhibited by regulating the epidermal growth factor receptor (EGFR)–tumor necrosis factor receptor (TNFR) signaling pathway in necroptosis. By delineating the underlying mechanisms of these receptors, we propose that the induction of necroptosis via EGFR and TNFR represents an innovative paradigm for targeted therapy, offering a strategy to enhance clinical outcomes in treatment-resistant cancers. Full article

Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), limiting the durability of targeted therapy. Bardoxolone methyl (CDDO-Me) has been reported to exert anti-inflammatory and anti-cancer activities. However, its role in acquired EGFR-TKI resistance remains unclear. Here, we found that CDDO-Me significantly enhanced sensitivity of resistant NSCLC cells to gefitinib, with combination index analysis confirming a synergistic interaction between CDDO-Me and gefitinib. Mechanistically, CDDO-Me induced mitochondrial dysfunction and reactive oxygen species (ROS) accumulation, thereby activating Caspase-3 mediated apoptosis and GSDME-dependent pyroptosis, as evidenced by increased lactate dehydrogenase (LDH) release. Network pharmacology and molecular docking analyses identified Src as a potential target of CDDO-Me. Cellular thermal shift assay (CETSA) confirmed cellular engagement between CDDO-Me and Src, and Western blot analysis showed that CDDO-Me suppressed Src/STAT3 signaling. Consistently, Src knockdown reduced the inhibitory effect of combined CDDO-Me and gefitinib treatment on colony formation and attenuated changes in apoptosis and pyroptosis regulatory proteins induced by the combination treatment. Collectively, these findings suggest that CDDO-Me enhances gefitinib sensitivity by targeting Src and suppressing Src/STAT3 signaling, leading to apoptosis and pyroptosis in gefitinib-resistant NSCLC cells. This study provides mechanistic evidence for further investigation of CDDO-Me-based combination strategies for gefitinib-resistant NSCLC. Full article

Approximately half of Japanese patients with lung adenocarcinoma (LUAD) have epi-dermal growth factor receptor (EGFR) gene mutations. Therefore, EGFR is the most critical therapeutic target in treating LUAD. This study’s purpose is to explore novel therapeutic targets for LUAD and further improve EGFR inhibitor combination therapy. We created microRNA (miRNA) expression signatures from clinical specimens of LUAD patients harboring EGFR gene mutations using RNA sequencing. Based on the miRNA signature, we focused on miR-206, which had the most downregulated expression. We searched for its target gene in LUAD cells by facilitating transfection of miR-206 into the EGFR mutant cell line PC9 and searching for genes with suppressed expression. A total of 821 genes were downregulated in PC9 cells. Through molecular classification of these genes, we revealed that 18 genes were closely related to the cell cycle. Among these genes, we focused on cyclin-dependent kinase 4 (CDK4) and investigated the synergistic effects of a CDK4/6 inhibitor (abemaciclib or palbociclib) and osimertinib, an EGFR inhibitor in LUAD cells. In vitro and three-dimensional culture analyses showed that combination therapy with a CDK4/6 inhibitor and an EGFR inhibitor synergistically suppressed proliferation of LUAD cells with EGFR mutations. Our miRNA-based analysis is an excellent strategy for identifying therapeutic targets for LUAD. Continued analysis will reveal target molecules that enhance the therapeutic effects of EGFR inhibitors. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases and frequently associated with poor outcomes due to resistance to conventional therapies. The epidermal growth factor (EGF)–epidermal growth factor receptor (EGFR) axis plays a central role in NSCLC progression by activating downstream phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling, thereby promoting survival and proliferation. Natural compounds have emerged as promising modulators of these pathways, and oxyresveratrol (OXY), a hydroxylated analog of resveratrol, has been reported to possess antioxidant and anticancer properties, though its mechanistic role in NSCLC remains unclear. In this study, we investigated the effects of OXY in EGF-stimulated A549 and H1299 cells. OXY significantly reduced metabolic activity and decreased cell number in a dose-dependent manner and increased the proportion of apoptotic cells. Mechanistically, OXY selectively attenuated EGF-induced AKT phosphorylation while largely sparing extracellular signal–regulated kinase 1/2 (ERK1/2) activation and did not measurably alter EGFR phosphorylation or receptor trafficking dynamics. These findings indicate that OXY exposure is associated with AKT-selective signaling suppression and reduced cellular fitness in NSCLC cells, without evidence of direct EGFR inhibition. Further genetic rescue and pathway-epistasis studies are required to establish causal dependency on AKT signaling and to support in vivo validation. Full article

Mammary gland development during puberty requires tightly coordinated epithelial proliferation, lineage specification, and branching morphogenesis, processes critically regulated by growth factor signaling. While epidermal growth factor receptor (EGFR) signaling is essential for ductal development, how its activity is quantitatively controlled within mammary epithelial cells (MECs) remains incompletely understood. Here, we identify Rasgrp1, a Ras guanine nucleotide exchange factor, as a key modulator of EGFR signaling in the mammary epithelium. Using Rasgrp1-deficient mice, primary MEC assays, and organoid models, we demonstrate that loss of Rasgrp1 leads to elevated EGFR–Ras–PI3K–AKT and mTORC1-S6 signaling, resulting in enhanced proliferative capacity and aberrant EGF-driven branching. Transcriptomic analysis of organoids reveals that EGF signaling suppresses Wnt/R-spondin-dependent stem-cell gene programs, suggesting that excessive EGFR activity disrupts stem cell maintenance. In vivo, Rasgrp1 deficiency causes impaired ductal elongation, persistent terminal end buds, and increased epithelial proliferation, indicating a breakdown in the spatial and temporal coordination of mammary morphogenesis. Together, our findings establish Rasgrp1 as a signaling rheostat that dampens EGFR pathway activity to support coordinated mammary gland development. These results highlight the importance of precise signaling calibration in epithelial development and suggest broader implications for Ras pathway regulation in tissue homeostasis and disease. Full article

Background/Objectives: Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has undergone rapid therapeutic evolution. However, heterogeneous outcomes persist, driven by mutations, central nervous system (CNS) involvement, and dynamic tumor burden reflected in part by circulating tumor DNA (ctDNA). As such, this review aims to summarize the most recent risk stratification frameworks in treating EGFR-mutant NSCLC, evaluate evidence supporting treatment intensification strategies and managing adverse effects, and explore the evolving role of ctDNA in guiding personalized therapy. Methods: A comprehensive literature search was conducted using major medical databases with a focus on key relevant studies on the workup and management of EGFR-mutant NSCLC. All authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Molecular co-alterations, such as TP53 and RB1, as well as central nervous system (CNS) involvement, are consistently associated with inferior outcomes, supporting consideration of upfront treatment intensification. Combination strategies, including osimertinib plus chemotherapy or amivantamab-based regimens, demonstrate improved progression-free survival and delayed CNS progression when compared against osimertinib monotherapy. Intensification, however, is associated with a higher risk of increased toxicity, including dermatologic adverse events and infusion-related reactions. Finally, the utilization of circulating tumor DNA (ctDNA) has emerged as a strong prognostic marker, with ongoing trials investigating its predictive role for both escalation and de-escalation of therapy. Conclusions: The treatment paradigm for EGFR-mutant NSCLC is gradually evolving beyond first-line osimertinib to include a more integrated approach that considers molecular features, CNS involvement, and early ctDNA response. Although intensified regimens offer meaningful efficacy gains for high-risk patients, proactive toxicity management is essential to preserving quality of life. ctDNA-guided strategies represent a new and promising frontier for escalation and de-escalation of therapy, with results from ongoing trials poised to further refine personalized treatment algorithms. Full article

Background: Colorectal cancer (CRC), a leading cause of cancer-related mortality worldwide, necessitates improved non-invasive diagnostic and monitoring tools. Circulating tumor cells (CTCs), as intact cellular biomarkers in liquid biopsies, offer valuable morphological and genetic information and hold significant clinical potential for early detection, prognosis, therapy monitoring, and drug development. Bio-ferrography is a non-invasive immunomagnetic separation technique that isolates magnetically labeled entities from fluid samples onto a glass substrate via a focused external magnetic field. Methods: This study employs, for the first time, bio-ferrography for isolation, counting, and microscopic characterization of circulating tumor cells (CTCs) expressing the human epidermal growth factor receptor (EGFR) from blood biopsies taken from patients in the hospital. Magnetic beads conjugated with anti-EGFR antibodies were used to selectively capture CTCs from peripheral blood samples of patients with metastatic CRC and other epithelial malignancies. The method enabled both enumeration and microscopic characterization of isolated cells. Results: Preliminary clinical results demonstrate that bio-ferrography achieves a sensitivity of 90% in stage-IV patients and exhibits higher true positive detection rates compared to conventional tumor biomarkers, including carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA). Conclusions: These findings highlight the potential of bio-ferrography as a robust platform for CTC isolation and analysis. Full article

Epithelial–mesenchymal transition (EMT) emerged as a phenotypic change associated with the resistance to epidermal growth factor receptor tyrosine kinase inhibitors, both in vitro and in vivo. The mechanisms underlying this biological process have not yet been fully understood. E-cadherin loss, N-cadherin, and vimentin increase are the main markers characterizing EMT, together with the expression of some transcription factors, such as Snail, Slug, Zeb1, Zeb2, and Twist. In this study, we explore the expression of these markers in lung cancer cell lines bearing wild-type or mutated epidermal growth factor receptor (EGFR), A549 and PC9, respectively. We treated PC9 cells with Gefitinib or Osimetinib, alone or combined with the transforming growth factor beta (TGF-β). We evaluated the expression of E-cadherin, N-cadherin, vimentin, and the transcription factors at 24 and 96 h timepoints, to verify the role of EMT in the early phases of the treatment with tyrosine kinase inhibitors (TKIs). At the 96 h timepoint, we found that in PC9 cells, the treatment with gefitinib or osimertinib, regardless of TGF-β, induces E-cadherin reduction and N-cadherin increase, similar to the effects induced by TGF-β in A549 cells at 24 h. Among the transcription factors, at 96 h, Slug mainly increases when PC9 cells are treated with gefitinib or osimertinib. These results imply that changes in the expression of these epithelial–mesenchymal transition markers may have facilitated the development of drug resistance. Full article