Search Results (4,944)

Background/Objective: In lung cancer treatment, increasing the concentration of antitumor drugs at the tumor site, enhancing efficacy, and reducing systemic toxicity are significant challenges. This study aims to develop an intelligent responsive polymer micelle system (GPDD) that achieves efficient accumulation and controlled release of drugs at lung tumor sites through targeted and pH-responsive design. Methods: The GPDD system is formed by the self-assembly of GE11-PEG-hyd-DOX conjugates and co-loads free DOX. This system utilizes the targeting effect of the GE11 peptide with the epidermal growth factor receptor (EGFR) to accumulate at the tumor site, while the hydrazone bond serves as a pH-responsive linker that breaks in the acidic tumor microenvironment, triggering drug release. Experiments employed CCK-8 cytotoxicity assays and tumor-bearing nude mouse models (strain not specified) for in vitro and in vivo evaluations. Results: In vitro experiments showed that GE11-modified GPDD effectively inhibited tumor cell growth. In tumor-bearing nude mouse experiments, GPDD demonstrated more significant tumor suppression effects and lower systemic toxicity compared to free DOX and unmodified PDD. Conclusions: The GPDD nanocarrier integrates targeting and pH responsiveness, improving antitumor efficacy and reducing side effects, with translational potential. The novelty of the study lies in its dual-functional design and co-loading strategy, providing new insights for tumor-targeted delivery systems. Full article

Background/Objectives: Precise intracellular delivery of chemotherapeutics remains a major challenge in HER2-positive breast cancer, where intratumoral heterogeneity and limited tissue penetration constrain efficacy. A key contributor is the tumor-restricted epidermal growth factor receptor variant III (EGFRvIII), a constitutively active, ligand-independent mutant generated by deletion of exons 2–7. Although classically associated with glioblastoma, lung (NSCLC), head/neck, and prostate cancers, EGFRvIII is also present in subsets of HER2-positive breast cancers, where low-abundance subclones drive aggressive phenotypes and attenuate therapeutic responses. HER2–EGFRvIII co-expression amplifies oncogenic signaling, supported by frequent co-expression in ErbB2-positive primary tumors and metastases, and by sustained receptor phosphorylation in the absence of EGFR gene amplification, depicting EGFRvIII as a compelling therapeutic target. Methods: We evaluated the shark-derived single-domain antibody vNAR R426 as a modular theranostic platform for receptor-mediated cisplatin delivery. Conjugation to cisplatin and fluorescein enabled simultaneous intracellular drug transport and immunofluorescence-based detection in EGFRvIII-positive SKBR3 cells and 3D spheroids. The compact vNAR-based immunoconjugates support efficient receptor recognition, internalization, and intracellular trafficking, features rarely achieved by conventional IgG antibodies. Results: vNAR_CDDP elicited robust, receptor-mediated cytotoxicity, achieving an IC₅₀ of 2.68 µM—approximately 50-fold lower than that of free cisplatin—while unconjugated vNAR maintained scaffold biocompatibility. In three-dimensional spheroid models, the theranostic vNAR (vNAR_CDDP+FITC) exhibited deep and uniform penetration throughout tumor-like architectures, with immunofluorescence intensity closely correlating with regions of intracellular drug delivery and the initiation of cytotoxic responses. Notably, cisplatin conjugation did not impair tissue diffusion or receptor engagement, facilitating effective payload delivery to both peripheral and central cell populations. Conclusions: By integrating tumor-restricted targeting and efficient intracellular drug delivery within a modular single-domain scaffold, vNAR R426 represents a next-generation theranostic platform capable of addressing intratumoral heterogeneity. This approach combines potent cytotoxic activity with immunofluorescence-based detection, thereby advancing the rational design of precision therapeutics for HER2-positive breast cancer. Full article

Glycosylation is one of the most prevalent post-translational modifications of membrane proteins and plays a central role in regulating their structure and function. Unlike many existing reviews that address glycosylation in a system-wide context, this review focuses specifically on membrane proteins and examines how glycosylation shapes their functional behavior and clinical relevance. Because membrane proteins are exposed to the extracellular environment, glycans on their surface directly influence protein folding, receptor organization, and interactions with ligands and immune components. These diverse effects can be understood within a common mechanistic framework in which glycosylation modulates protein conformation, receptor clustering, and membrane organization, thereby altering signaling, adhesion, transport, and immune recognition. We discuss how N-linked and O-linked glycosylation regulate major classes of membrane proteins across these processes. Particular attention is given to disease-associated alterations in glycosylation, especially in cancer, immune and inflammatory disorders, and metabolic disease. For instance, glycosylation-dependent stabilization of PD-L1 and modulation of receptor signaling, such as EGFR, illustrate how glycan modifications contribute to immune evasion and therapeutic response. We further consider the clinical implications of membrane protein glycosylation, including its roles in biomarker development and as a potential target for therapeutic intervention. Advances in glycoproteomic technologies have enabled increasingly detailed characterization of site-specific glycosylation, although significant analytical challenges remain, particularly for membrane proteins. Overall, this review highlights membrane protein glycosylation as a dynamic regulatory layer that links molecular mechanisms to functional outcomes and clinical applications. Full article

Background: Clinical tools to structure kidney transplant waitlist management at the time of listing are limited. We evaluated a simple, donor-independent clinical grading applied at waitlist registration to stratify patients according to post-transplant risk. Methods: We retrospectively analyzed 465 adult kidney transplant recipients from two German centers (2018–2023). Patients were assigned to three clinical grading groups based on age and comorbidities, and to three immunologic groups based on pre-immunization. One-year outcomes included mortality, graft loss, eGFR, albuminuria, and rejection. Results: Higher clinical grades were associated with worse one-year outcomes, including lower eGFR and higher rates of death or graft loss, whereas immunologic grading was associated with waiting time but not short-term post-transplant outcomes. These associations appeared robust to donor characteristics in sensitivity analyses. Conclusions: A simple, listing-time clinical grading may support structured waitlist management before donor information is available. External validation is required. Full article

Background: Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and remains a major health concern due to its high recurrence and mortality rates. Recent studies suggest that anesthetic agents, including ketamine, may have direct effects on cancer cell viability and apoptosis. Objective: This study aimed to investigate the in vitro effects of ketamine on the HT-29 human colorectal adenocarcinoma cell line, focusing on its cytotoxic and pro-apoptotic potential. Material and Methods: HT-29 cells were treated with ketamine for 24 h. Cell viability was evaluated using the MTT assay. Apoptosis rates were determined by flow cytometry with Annexin V-FITC/7-AAD staining. Furthermore, quantitative PCR (qPCR) was performed to assess the expression levels of key genes associated with proliferation and apoptosis. GeneQuery™ Human Basal Cell Carcinoma qPCR Array Kit (GQH-BCC-GK015-C) was used for qPCR analysıs. Molecular docking simulations were performed to investigate the potential molecular interactions between ketamine and three target proteins: the N-methyl-D-aspartate (NMDA) receptor, epidermal growth factor receptor (EGFR), and casein kinase 1 delta (CSNK1D). To ensure robustness of predictions, two independent docking methods were employed. Results: Ketamine significantly reduced cell viability in a dose-dependent manner, with an IC₅₀ value of approximately 1.05 µM. Flow cytometry analysis demonstrated a marked increase in early apoptosis (23.9%) in treated cells. These findings suggest that ketamine exhibits potential anti-proliferative and pro-apoptotic effects on HT-29 colorectal cancer cells. Conclusions: These findings suggest that ketamine exhibits potential anti-proliferative and pro-apoptotic effects on HT-29 colorectal cancer cells in vitro. Further studies are warranted to elucidate the underlying molecular mechanisms and potential clinical implications. Full article

Non-Small-Cell Lung Cancer (NSCLC) represents the most prevalent form of lung cancer and remains one of the leading causes of cancer-related morbidity and mortality worldwide. This disease has evolved far beyond traditional histopathological classification. While histology remains foundational, it is no longer sufficient to guide optimal patient management in the era of precision oncology. This review uniquely integrates the full spectrum of NSCLC evaluation, from underlying pathophysiological mechanisms to histological, immunohistochemical, and molecular analyses, culminating in individualized therapeutic planning. We highlight actionable genetic alterations—including EGFR, ALK, ROS1, BRAF, and KRAS—and their roles in guiding targeted therapies, alongside the transformative impact of immune checkpoint inhibitors in selected patients. By emphasizing the interplay between tumor biology, diagnostic workflows, and treatment selection, this review underscores the necessity of comprehensive molecular testing and data integration. Finally, we discuss emerging biomarkers and rational combination strategies that promise to further refine patient stratification and improve outcomes. Full article

Background and Objactives: Metformin is the most widely prescribed glucose-lowering therapy worldwide and is generally considered safe in patients with chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m². However, very elderly patients are underrepresented in pivotal trials, and evidence on metformin safety in this vulnerable population remains limited. We evaluated the association between metformin use and adverse clinical outcomes in very elderly patients with CKD and type 2 diabetes. Materials and Methods: We conducted a single-center retrospective observational study including 624 very elderly patients (age > 78 years) with CKD, type 2 diabetes mellitus, and eGFR > 30 mL/min/1.73 m². Patients were stratified according to metformin exposure (309 metformin-treated and 315 controls). The primary composite outcome was the first occurrence of intensive care unit (ICU) admission, initiation of renal replacement therapy (RRT), lactic acidosis, or all-cause mortality. A propensity score-matched sensitivity analysis and hierarchical win ratio analysis were also performed to further address potential baseline confounding. Results: Over a median follow-up of 33.7 months, the primary composite outcome occurred more frequently in the metformin group than in controls (18.7% vs. 9.5%; HR 1.75; 95% CI 1.12–2.73; p = 0.013). Metformin use was associated with a higher risk of ICU admission (HR 2.33; 95% CI 1.33–4.08), RRT initiation (HR 1.90; 95% CI 1.14–3.16), and lactic acidosis (HR 3.14; 95% CI 1.75–5.65). All-cause mortality was numerically higher but not statistically significant (HR 1.57; 95% CI 0.89–2.78). In a propensity score-matched analysis including 260 matched pairs, the association between metformin exposure and adverse outcomes remained consistent, and hierarchical win ratio analysis favored the control group (win ratio 2.00; 95% CI 1.24–3.47). Conclusions: In very elderly patients with CKD and type 2 diabetes, metformin use was associated with a higher observed risk of adverse clinical outcomes. These findings support a cautious, individualized risk–benefit assessment when prescribing metformin in this population. Full article

Background: Dodder, the dried mature seed of Cuscuta chinensis Lam. (CCL), has demonstrated anti-tumor activity, but its molecular and immunological mechanisms in clear cell renal cell carcinoma (ccRCC) remain unclear. Objective: To identify potential targets and elucidate the immune mechanisms by which CCL exerts therapeutic effects against ccRCC. Methods: A network pharmacology approach was employed to predict CCL’s bioactive components and their putative targets in ccRCC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to explore relevant pathways. Molecular docking validated the binding of key compounds to hub proteins. In vitro assays—including cell viability, colony formation, invasion, and apoptosis measurements—assessed the effects of quercetin, a principal CCL constituent, on 786-O renal carcinoma cells. Flow cytometry was performed to determine the percentage of CD163⁺ cells. An in vivo xenograft model evaluated CCL’s anti-tumor efficacy. Western blotting, flow cytometry, and multiplex immunohistochemistry (mIHC) examined the modulation of signaling pathways and immune cell markers. Results: Network pharmacology identified IL-6, EGFR, TLR4, MMP9, CD44, and IFN-γ as core targets of CCL in ccRCC. Enrichment analyses implicated immune regulation, inflammation modulation, and PI3K/AKT signaling inhibition. Molecular docking revealed strong quercetin–MMP9 binding affinity. Immuno-correlation analyses indicated that high MMP9 levels positively correlated with macrophage infiltration and M2 polarization, suggesting a role in tumor immune escape. Quercetin significantly reduced the viability of 786-O cells in a dose-dependent manner, showing approximately 45% inhibition at 80 μM (p < 0.01). In addition, quercetin decreased MMP9 expression and reduced the proportion of CD163-positive macrophages. These effects were reversed by FSL-1 TFA (Toll-like receptor 2/6 agonist), which is the agonist of MMP-9. In the xenograft model, tumor volume in the quercetin-treated group was reduced by approximately 50% compared with the control group. Conclusions: CCL, particularly its active component quercetin, may inhibit ccRCC progression via inhibiting MMP9-mediated M2 macrophage polarization. Full article

Background: Hepatitis B virus (HBV) infection continues to be a major public health concern, especially in sub-Saharan Africa, where widespread epidemics and restricted availability of long-term antiviral therapies result in higher mortality and morbidity rates. Drug repurposing represents a strategic approach to accelerate the discovery of effective therapies by leveraging agents with demonstrated antiviral and immunomodulatory activity. Product Nkabinde (PN) is a patented African polyherbal formulation initially developed for the treatment of HIV. Recent experimental studies demonstrate PN’s potent anti-HIV activity and significant immunomodulatory effects in human immune cells, implicating host-directed mechanisms relevant to chronic viral infections. This study combines an integrative application of network pharmacology and molecular docking to evaluate the repurposing potential of PN as a multi-target agent in HBV. Method: Bioactive components of PN were screened, and compound-associated targets were intersected with HBV-associated genes (proteins) to construct a protein–protein interaction (PPI) network. Topological analysis identified 10 hub targets (STAT1, STAT3, SRC, HCK, EGFR, SYK, PIK3CA, PIK3CB, PIK3R1, and PTPN11). Gene Ontology and KEGG pathway enrichment were performed with an FDR cut-off < 0.05. Significantly enriched pathways included JAK–STAT signaling, chemokine signaling, EGFR-TKI resistance, PI3K complex signaling, and viral infection pathways, particularly those related to Kaposi sarcoma virus and HSV-1, indicating immunoregulatory and antiviral roles. Molecular docking was performed using AutoDock Vina 1.1.2 to evaluate binding affinity and interaction mode of key PN phytochemicals against the hub proteins, and results were compared to their respective co-crystallized ligands. Results: Molecular docking indicated that major phytochemicals from PN exhibited significant binding affinities across all 10 hub host targets, typically outperforming or closely matching their respective co-crystallized ligands. The strongest contacts were observed for β-sitosterol–PIK3CB (−14.2 kcal/mol) and oleanolic acid–SYK (−14.0 kcal/mol), which were significantly stronger than the co-crystallized ligands (−7.9 and −8.3 kcal/mol, respectively), indicating robust stabilization within catalytic and regulatory pockets. Procyanidin B2 toward HCK (−10.5 vs. −7.9 kcal/mol) and PIK3CA (−9.5 vs. −7.3 kcal/mol), quercetin toward PIK3R1 (−10.6 vs. −8.2 kcal/mol) and PTPN11 (−9.2 vs. −7.5 kcal/mol), rutin toward SRC (−10.5 vs. 7.8 kcal/mol), and diosgenin toward EGFR (−9.4 vs. 8.4 kcal/mol). Procyanidin B2 maintained robust multi-hydrogen bonding networks, demonstrating significant binding, despite STAT1 and STAT3 docking showing identical affinities to co-crystals. Conserved hydrogen bonds, π–cation interactions, and significant hydrophobic packing at ATP-binding clefts and regulatory domains supported these interaction patterns, indicating competitive suppression of host signaling nodes taken over by HBV. Conclusions: Together, these results demonstrate that the components of PN possess strong multitarget binding capabilities across the PI3K/AKT, JAK–STAT, SRC-family kinase, EGFR, and SYK pathways, supporting their potential repurposing as host-directed HBV therapeutics with the ability to impede immune evasion, viral persistence, and HBV-associated oncogenic progression. Full article

Background/Objectives: Given the narrow therapeutic range of tacrolimus and substantial inter-individual variability in trough levels, both total daily dose and the trough level-to-dose ratio are commonly used to guide dose optimization. In this study, Life-Cycle Pharma tacrolimus was compared with immediate-release tacrolimus in a real-world setting. Methods: This longitudinal observational study included kidney transplant recipients at two Hungarian university clinics. Sixty-three (63) patients completed the study and were included in the statistical analysis. They received either Life-Cycle Pharma-tacrolimus (n = 40) or immediate-release tacrolimus (n = 23) as maintenance therapy in the two study arms, each combined with everolimus or mycophenolic acid and corticosteroids. Patients were enrolled 4–6 weeks after transplantation and prospectively followed for 48 months. Tacrolimus trough level, total daily dose and their ratio were recorded at each of the seven follow-up visits during the 48-month study period. Epidemiological data, patient characteristics, laboratory parameters (including eGFR, de novo donor-specific antibodies, and CMV and BK virus incidence), and acute rejection episodes were monitored. Results: The mean age at enrolment was 53.35 years, and 41 patients (65.08%) were male. A stable therapeutic maintenance trough level was achieved in both study arms. Life-Cycle Pharma tacrolimus required a 30% lower total daily dose than immediate-release tacrolimus to achieve comparable exposure. A gradual decline in eGFR was observed in the immediate-release tacrolimus arm (a mean decrease of 6.06 mL/min/1.73 m² over 4 years) from a baseline level of 58.52 mL/min/1.73 m² (±16.69), whereas GFR increased in the Life-Cycle Pharma tacrolimus arm (a mean increase of 4.76 mL/min/1.73 m² over the same period) from a significantly lower baseline level of 46.55 mL/min/1.73 m² (±17.04). Conclusions: Both formulations provided effective long-term maintenance immunosuppression in kidney transplant recipients and maintained stable trough levels. Life-Cycle Pharma tacrolimus represents a potential option for dose minimization, and it also helped to stabilize renal function despite the worse baseline condition. Full article

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and remains a leading cause of cancer-related mortality worldwide. Advances in molecular characterization and tumor biology have driven the development of antibody-based therapies targeting immune checkpoints, angiogenesis, and oncogenic signaling pathways critical for tumor growth and progression. Among these agents, Ramucirumab, Atezolizumab, and Amivantamab have demonstrated significant clinical efficacy in selected NSCLC populations. This review summarizes the mechanisms of action, pivotal clinical trials, and current clinical evidence supporting the use of ramucirumab, atezolizumab, and amivantamab in the management of advanced NSCLC. Relevant literature was identified through searches of PubMed, clinical trial registries, and recent international conference proceedings, with an emphasis on therapeutic efficacy, safety profiles, and rational combination strategies. Ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor-2 (VEGFR-2), has shown a survival benefit when combined with docetaxel in patients with previously treated advanced NSCLC. Atezolizumab, a programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor (ICI), has become a cornerstone of NSCLC treatment across multiple disease stages, both as monotherapy and in combination with chemotherapy. Amivantamab, a bispecific antibody targeting both epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET), has demonstrated robust and durable clinical activity in patients with EGFR exon 20 insertion–mutated NSCLC. Collectively, these agents highlight the expanding role of antibody-based therapies in NSCLC and underscore the importance of biomarker-driven patient selection and treatment personalization. Ongoing research into resistance mechanisms, predictive biomarkers, and combination approaches is expected to further refine the integration of antibody-based strategies in precision oncology for NSCLC. Full article

Background/Objectives: Protein kinases play a crucial role in cancer initiation, progression, and therapeutic resistance by regulating signalling pathways involved in tumour growth and survival. Consequently, they represent major targets in anticancer drug discovery. Among heterocyclic scaffolds explored in kinase inhibitor design, benzimidazole has emerged as a privileged structure due to its strong hydrogen-bonding capability and structural resemblance to purine moieties. Triazole motifs are also widely incorporated into bioactive molecules because of their metabolic stability, favourable electronic properties, and ability to establish key interactions within kinase active sites. This review aims to summarise and critically discuss benzimidazole- and triazole-based kinase inhibitors, both as individual scaffolds and as hybrid systems, with emphasis on their kinase targets and multitarget potential. Methods: The relevant literature was surveyed from major scientific databases focusing on studies describing the synthesis, biological evaluation, and molecular modelling of benzimidazole- and triazole-containing kinase inhibitors. Results: Numerous studies demonstrate that both benzimidazole and triazole scaffolds exhibit significant kinase inhibitory activity against oncogenic targets, including EGFR, cyclin-dependent kinases (CDKs), and components of the PI3K/Akt/mTOR signalling pathway. Hybrid molecules combining these pharmacophores frequently enhance binding interactions and facilitate the development of multitarget kinase inhibitors. Structure–activity relationship trends indicate that pharmacophore accessibility, substitution patterns, and linker architecture influence inhibitory potency and selectivity. Conclusions: Overall, benzimidazole- and triazole-based scaffolds represent promising platforms for developing next-generation multitarget anticancer agents and provide valuable insights for the rational design of improved kinase inhibitors. Full article

Background: Early postoperative changes in creatinine-based estimated glomerular filtration rate (eGFR) after bariatric surgery can be misread as a kidney injury. During rapid weight loss, indexing eGFR to a fixed body surface area (BSA) of 1.73 m² may alter apparent trajectories. We compared absolute (mL/min) and BSA-indexed (mL/min/1.73 m²) eGFR changes after sleeve gastrectomy, stratified by baseline glomerular hyperfiltration (GH). Methods: In this retrospective cohort of 145 adults undergoing laparoscopic sleeve gastrectomy, serum creatinine was obtained at baseline (≤30 days pre-op) and 3 months (post-op days 75–105). Indexed eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 creatinine equation; BSA with the Mosteller formula; and absolute eGFR as indexed eGFR × (BSA/1.73). GH was defined as indexed eGFR ≥ 120 mL/min/1.73 m². A REML mixed-effects model (Group, Time, Group × Time) with patient-cluster bootstrap inference was used. An age-adjusted sensitivity model including Age and Age × Time was also fitted. Results: Fifty-four participants (37%) met the GH criteria. Absolute eGFR declined by −26.6 mL/min in GH versus −17.3 mL/min in non-GH (difference-in-differences [DiD] −9.3 mL/min; 95% CI −13.9 to −4.7; p < 0.001). The indexed eGFR changes were smaller (−4.2 vs. −0.5 mL/min/1.73 m²; DiD −3.7; 95% CI −7.3 to −0.03; p = 0.048; bootstrap p_sign = 0.052). In the age-adjusted sensitivity model, the Group × Time interaction for absolute eGFR attenuated but remained statistically significant (−6.57 mL/min; 95% CI, −13.09 to −0.06; p = 0.048), whereas the corresponding interaction for indexed eGFR was attenuated and no longer statistically significant (−3.99 mL/min/1.73 m²; 95% CI −9.15 to 1.16; p = 0.129). Conclusions: Within three months after sleeve gastrectomy, participants with higher baseline indexed filtration showed a larger decline in absolute eGFR but only a small change in indexed eGFR. These results show that early postoperative creatinine-based eGFR trajectories are scale dependent and should be interpreted cautiously during rapid weight loss. Because postoperative acute kidney injury (AKI) was not adjudicated and direct kidney function markers were unavailable, this study does not distinguish physiological hemodynamic change from structural kidney injury. Reporting both absolute and indexed eGFR may improve early postoperative interpretation and help align dosing decisions with rapid changes in body size. Full article

Metastatic colorectal cancer (mCRC) remains one of the leading causes of cancer-related mortality worldwide despite substantial therapeutic improvements over the past two decades. Advances in the understanding of colorectal tumor biology and oncogenic signaling have enabled the development of biomarker-guided therapies targeting alterations in EGFR, BRAFV600E, KRAS mutations and HER2 amplifications, improving outcomes in selected patient populations. Nevertheless, the emergence of both intrinsic and acquired resistance mechanisms continues to limit the durability of these responses. Resistance to targeted therapies in mCRC arises through multiple, often convergent mechanisms, including activation of compensatory signaling pathways, pre-existing genomic heterogeneity, and therapy-driven clonal selection. The integration of molecular profiling into clinical decision-making is essential to guide treatment selection and optimize therapeutic sequencing, ultimately enabling progress in precision oncology. Advances in genomic technologies, particularly circulating tumor DNA (ctDNA) analysis, have allowed longitudinal monitoring of tumor evolution, providing important insights into the mechanisms underlying resistance to targeted therapies. The aim of this review is to summarize the genomic landscape of mCRC and discuss current targeted therapeutic strategies in molecularly defined subgroups, with a particular focus on the mechanisms driving primary and acquired resistance. Full article

Epidermal growth factor receptor (EGFR)-kinase domain duplication (KDD) represents an atypical mutation distinct from classical EGFR mutations in lung adenocarcinoma (LUAD). Although first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity in EGFR-KDD, the mechanisms of acquired resistance in this setting remain poorly characterized. Herein, we present a LUAD patient with EGFR-KDD who achieved a sustained initial response to afatinib lasting 67 months before developing acquired resistance. Re-biopsy with next-generation sequencing (NGS) uncovered EGFR T790M, accompanied by EGFR amplification and EGFR M766T. The patient was switched to firmonertinib, with subsequent tumor regression. We reviewed published EGFR-KDD cases that had both acquired resistance to first- or second-generation EGFR-TKIs and corresponding repeat biopsy findings. Five of the eleven cases harbored EGFR T790M, yielding a prevalence of 45%, which is similar to that seen in classical EGFR mutations. This case suggests that EGFR T790M mediates acquired resistance to first- and second-generation EGFR-TKIs in EGFR-KDD, mirroring the resistance pattern observed in classical EGFR mutations. Full article