Since cancer biomarkers for lung adenocarcinoma can lead to early intervention and treatment, they have been the focus of much research attention. DNA aptamers, which are functional oligonucleotides, exhibit high specificity and binding affinity to different types of cancer biomarkers. Through DNA aptamer screening, a leucine-rich PPR-motif-containing protein (LRPPRC) was discovered as a potential biomarker for lung adenocarcinoma therapeutics. It is an RNA-binding protein that helps in regulating post-transcriptional gene expression in mitochondria. Interestingly, the first LRPPRC-targeted small-molecule drug showed significant antitumor effects. Apart from biomarker discovery, DNA aptamers have also shown promise in cancer therapeutics, but challenges in the programmable delivery of aptamers have limited applications. Herein, we have addressed these challenges in two steps. First, after obtaining purified protein LRPPRC, we verified aptamer R14 as its high-affinity binding ligand. Second, for programmable delivery, a rectangular DNA tile (RDT) was constructed to improve cellular internalization. In particular, DNA handles on the surface of this DNA nanostructure serve as overhangs for loading multivalent R14, and both A549 and PC9 cells treated with R14-RDT targeted to LRPPRC showed significant inhibition of cancer cell proliferation. We then investigated the molecular mechanism(s) underlying the interaction between multivalent aptamer R14 loaded on an RDT and its cognate target protein such that the result is inhibition of cancer cell proliferation. Based on our findings, we hypothesized that R14-RDT-LRPPRC interaction triggers significant gene transcription and RNA processing events that result in inhibiting mitochondria-related genes and RNA transcriptional processing, while causing an immune inflammatory response that ultimately leads to the inhibition of cancer cell proliferation. Therefore, this research offers an instructive paradigm for programmable loading of a multivalent aptamer onto a two-dimensional DNA nanostructure to improve targeted cancer therapeutics through intervening with the cell's transcriptome.

CEACAM family proteins have been extensively studied as cell adhesion molecules, yet the biological and clinical significance of CEACAM6 remains relatively unexplored. Our research identifies a significant increase in CEACAM6 expression in lung adenocarcinoma, particularly correlating with EGFR mutation status. In EGFR-mutated lung cancer cells, CEACAM6 knockdown induced apoptosis and reduced p-ERK1/2 signaling downstream of EGFR. Treatment with EGFR-tyrosine kinase inhibitors (TKIs) decreased CEACAM6 levels, leading to TKI-resistant lung cancer cells that exhibited reduced p-ERK1/2 and increased epithelial-mesenchymal transition (EMT) characteristics. Co-immunoprecipitation assays revealed an interaction between CEACAM6 and EGFR. Although CEACAM6 expression was lost in EGFR-TKI resistant cells, its re-expression stabilized EGFR and increased sensitivity to EGFR-TKIs. TGF-β treatment, which induced EMT, also decreased CEACAM6 expression and improved EGFR-TKI resistance. Further analysis showed that EGFR-TKI resistant lung cancer cells had lower H3K27ac epigenetic modification levels at the CEACAM6 locus than EGFR-TKI sensitive cells. Treatment with HDAC1/2 inhibitors in EGFR-TKI sensitive cells reduced CEACAM6 expression, induced EMT and TGF-β-ligand/receptor gene expression, and enhanced EGFR-TKI resistance. These data highlight the crucial role of CEACAM6 in maintaining oncogenic EGFR signaling and its regulation by cytokine stimulation and epigenetic modification, influencing EGFR-TKI sensitivity. Our findings underscore CEACAM6's potential as a valuable biomarker in EGFR-driven lung adenocarcinoma and its intricate involvement in EGFR-related pathways.

The resistance of growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC), especially against the EGFR L858R/T790M/C797S mutations, remains an ongoing challenge. In this study, we screened a total of 2.05 million compounds from the ChEMBL database through virtual screening, identifying five promising candidates with high binding affinities and favourable ADMET properties. These candidates were further evaluated through molecular dynamics (MD) simulations, revealing more restricted conformational changes and enhanced stability compared to Osimertinib. Protein-ligand interaction analyses highlighted a broader range of stabilizing interactions in the binding domain. Additionally, the binding free energies of the compounds showed that compounds 1-5 ranged from -34.95 to -45.54 kcal/mol, which were lower compared to Osimertinib (-34.49 kcal/mol), suggesting a stronger binding affinity. Subsequently, density functional theory (DFT) calculations provided further insights into the electronic properties of the compounds, which were essential for understanding the compounds' reactivity and potential interactions with the target protein. In conclusion, the five identified compounds exhibit promising drug-like properties and may serve as lead candidates for the development of new treatments targeting EGFR L858R/T790M/C797S resistance mutations in NSCLC.

Twenty pyrimidine derivatives with aminophenylsulfonamide moiety were synthesized and evaluated as inhibitors against EGFR-mutation cancers. The anti-proliferation assay showed that most of the synthesized compounds had excellent inhibitory activity against H1975-EGFRL858R/T790M and PC9-EGFRDel19 tumor cells. Among them, the optimal compound 12e, exhibited 0.6 nM and 4 nM of the IC50 values against H1975 cells and PC9 cells, respectively. In PC9 and H1975 xenograft nude mice, TGI of 12e is 98.5 %and 97.7 % when oral administration at dosage of 20 mg/kg. Molecular docking study showed 12e gave preferable affinity upon EGFR then Osimertinib. As for the anti-tumor mechanism, 12e inhibits phosphorylation and downstream signaling by binding to EGFR, then inhibits the proliferation of tumor cell lines, promotes apoptosis, and prohibits the migration and invasion of the tumor cell lines.

Glioblastoma (GBM) is the most prevalent and aggressive primary brain malignancy in adults. Nevertheless, the cellular heterogeneity and complexity within the GBM microenvironment (TME) are still not fully understood, posing a significant obstacle in the advancement of more efficient immunotherapies for GBM. In this study, we conducted an integrated analysis of 48 tumor fragments from 24 GBM patients at the single-cell level, uncovering substantial molecular diversity within immune infiltrates. We characterized molecular signatures for five distinct tumor-associated macrophages (TAMs) subtypes. Notably, the TAM_MRC1 subtype displayed a pronounced M2 polarization signature. Additionally, we identified a subtype of natural killer (NK) cells, designated CD56dim_DNAJB1. This subtype is characterized by an exhausted phenotype, evidenced by an elevated stress signature and enrichment in the PD-L1/PD-1 checkpoint pathway. Our findings also highlight significant cell-cell interactions among malignant glioma cells, TAM, and NK cells within the TME. Overall, this research sheds light on the functional heterogeneity of glioma and immune cells in the TME, providing potential targets for therapeutic intervention in this immunologically cold cancer.

As a traditional Chinese medicine, Wu-Mei-Wan (WMW) has shown promise as a second-line treatment for gallbladder cancer, but its mechanism remains to be explored.

To determine the specific mechanism of WMW active ingredients (Palmatine et al.) inducing ferroptosis in gallbladder cancer (GBC) and its synergistic potential with gemcitabine.

Subcutaneous tumor in nude mice was used to analyze the combined effect of gemcitabine. The effective components into blood were identified by HPLC. Combined with proteomics, network pharmacology and bioinformatics analysis, the effective components and targets of WMW promoting ferroptosis in GBC were identified in vitro and in vivo. The anticancer effects of WMW on different GBC cell lines were evaluated by CCK-8 assay, colony formation and EdU staining. A variety of molecular biology experiments were used to explore the mechanism.

WMW treatment enhanced the sensitivity of GBC to gemcitabine, which induced ferroptosis and effectively inhibited the malignant phenotype of GBC. Network pharmacology and blood component identification identified the key components of WMW inhibiting GBC. Palmitine and other components were identified as active components into the blood. Proteomics and molecular docking validation further revealed the STAT3-centered regulatory network in GBC cells. Molecular experiments have shown that WMW induced ferroptosis by negatively regulating downstream molecules of p-STAT3 transcription of GPX4, ACSL4, HIF1α, and FTH1.

WMW induces ferroptosis in GBC through the p-STAT3 axis and enhances sensitivity to gemcitabine, suggesting the potential of WMW as a second-line therapeutic for GBC.

The epithelial-mesenchymal transition (EMT) is a critical process in cancer progression, facilitating tumor cells to develop invasive traits and augmenting their migratory capabilities. EMT is primed by tumor microenvironment (TME)-derived signals, whereupon cancer cells undergoing EMT in turn remodel the TME, thereby modulating tumor progression and therapeutic response. This review discusses the mechanisms by which EMT coordinates TME dynamics, including secretion of soluble factors, direct cell contact, release of exosomes and enzymes, as well as metabolic reprogramming. Recent evidence also indicates that cells undergoing EMT may differentiate into cancer-associated fibroblasts, thereby establishing themselves as functional constituents of the TME. Elucidating the relationship between EMT and the TME offers novel perspectives for therapeutic strategies to enhance cancer treatment efficacy. Although EMT-directed therapies present significant therapeutic potential, the current lack of effective targeting approaches-attributable to EMT complexity and its microenvironmental context dependency-underscores the necessity for mechanistic investigations and translational clinical validation.

Next-generation sequencing has revolutionized genome science over the last two decades. Indeed, the wealth of sequence information on our genome has deepened our understanding on cancer. Cancer is a genetic disease caused by genetic or epigenetic alternations that affect the expression of genes that control cell functions, particularly cell growth and division. Utilization of next-generation sequencing in cancer gene panels has enabled the identification of actionable gene alterations in cancer patients to guide personalized precision medicine.

The aim is to provide information that can identify actionable gene alterations, enabling personalized precision medicine for cancer patients.

Equipped with next-generation sequencing techniques, international collaboration programs on cancer genomics have identified numerous mutations, gene fusions, microsatellite variations, copy number variations, and epigenetics changes that promote the transformation of normal cells into tumors. Cancer classification has traditionally been based on cell type or tissue-of-origin and the morphological characteristics of the cancer. However, interactive genomic analyses have currently reclassified cancers based on systemic molecular-based taxonomy. Although all cancer-causing genes and mechanisms have yet to be completely understood or identified, personalized or precision medicine is now currently possible for some forms of cancer. Unlike the "one-size-fits-all" approach of traditional medicine, precision medicine allows for customized or personalized treatment based on genomic information.

Despite the availability of numerous cancer gene panels, technological innovation in genomics and expansion of knowledge on the cancer genome will allow precision oncology to manage even more types of cancers.

Non-small-cell-lung cancer (NSCLC) medication use and guideline adherence remain unclear. We investigated treatment patterns and adherence among Japanese patients with NSCLC.

We analyzed treatment patterns and guideline adherence by age and histology in ≥ 20-year-olds with stage IV NSCLC treated between 2016-2018 using diagnostic procedure combination data. Logistic regression analysis evaluated the impact of various factors on guideline adherence.

We included 9,722 patients. In < 75-year-olds with nonsquamous NSCLC, first-to third-line treatments comprised 31.8% platinum combination therapy, 26.3% immune checkpoint inhibitors, and 62.5% cytotoxic chemotherapy. In ≥ 75-year-olds, first-line and second-line molecular targeted therapies represented 46.6% and 35.6%, whereas third-line cytotoxic chemotherapy represented 42.3%. In squamous NSCLC, first-line platinum combination therapy was predominant (69.7% and 47.7% for < 75-and ≥75-year-olds). The most common second-line and third-line therapies were immune checkpoint inhibitors (48.6% and 50.8% for < 75-and ≥75-year-olds) and cytotoxic chemotherapy (62.5% and 55.2% for < 75-and ≥75-year-olds), respectively. The highest guideline adherence (90%) was in < 75-year-olds with squamous NSCLC. Age, histology, activities of daily living, and cumulative hospitalizations over the past 18 months influenced treatment adherence.

New NSCLC drug introduction increased regardless of age, suggesting prognosis improvement. More efficient drug application and broader guideline dissemination are required.

We identified 14 key genes associated with mitochondrial autophagy in sepsis through differential analysis of the dataset and then analysed the identified genes for functional enrichment. The analysis of key genes and deeper analysis of key genes by molecular typing, Weighted Gene Correlation Network Analysis (WGCNA) and ceRNA were also carried out. We have also validated these key genes with clinical data. Finally, sepsis diagnostic models are constructed by combining key genes with machine learning methods. In addition, we discuss the importance of the immune system in sepsis and its relationship with signature genes, which opens up new directions for studying the role of the immune system in sepsis. Overall, our study adds new ideas to the diagnosis and treatment of sepsis.

Small molecules targeting activating mutations within the epidermal growth factor receptor (EGFR) are efficacious anticancer agents, particularly in non-small cell lung cancer (NSCLC). Among these, lazertinib, a third-generation tyrosine kinase inhibitor (TKI), has recently gained FDA approval for use in combination with amivantamab, a dual EGFR/MET-targeting monoclonal antibody. This review delves into the discovery and development of lazertinib underscoring the improvements in medicinal chemistry properties, especially in comparison with osimertinib. Analysis of its structure-activity relationships (SAR), as outlined in the patent literature, reveals the structural diversity explored enroute to the candidate molecule. The resulting structure of lazertinib is distinguished among other TKIs due to the combination of the hydrophobic phenyl and hydrophilic amine substituents on the pyrazole. The structural basis for the selectivity against the T790M mutation is enabled by the substituted pyrazole moiety, which facilitates both van der Waals and H-bonding interactions with the EGFR kinase domain. Insights from this case study offer lessons that can inform the future design of kinase inhibitors with improved safety and efficacy profiles for cancer treatment and other diseases.

Recent advances in molecular oncology have increasingly illuminated the role of germline EGFR mutations in non-small cell lung cancer (NSCLC). This case report presents the presence of a unique familial occurrence of EGFR mutations in patients with NSCLC.

A mother and son, both never-smokers of Caucasian ethnicity, were diagnosed with advanced metastatic lung adenocarcinoma. In one patient, tumor molecular analysis by next generation sequencing (NGS) identified two EGFR mutations: the activating mutation c.2573T > G; p.Leu858Arg (p.L858R) in exon 21 of the EGFR gene, and the somatic non-pathogenic mutation c.2612 C > A; p.Ala871Glu (p.A871E) in exon 21 of the EGFR gene. The second patient also harbored the same two EGFR mutations. The patient underwent genetic testing which revealed the germline origin of the A871E mutation. Whether the presence of this mutations was associated with increased predisposition to cancer has yet to be determined. Our case report highlights the need for further exploration of the role of germline mutations, including the A871E mutation, in tumorigenesis and its implications for treatment response and inheritance patterns.

The investigation and comprehension of the significance of each individual EGFR mutation hold the promise for potential in cancer prevention or early diagnosis within family cohorts and understanding the mechanisms of tumorigenesis in sporadic cases.

This study seeks to identify research trends and hotspots concerning tyrosine kinase inhibitors (TKIs) for the treatment of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) through a comprehensive bibliometric analysis.

Publications on TKIs and EGFR-mutated NSCLC from 2006 to 2024 were analyzed using VOSviewer, CiteSpace, and R-bibliometrix to visualize collaboration, keyword co-occurrences, and research trends.

A total of 962 articles were analyzed, authored by 7,458 researchers from 5,401 institutions across 208 countries. Wu Yi-Long was identified as the most prolific author, contributing 30 publications. AstraZeneca emerged as the industrial leader with 103 articles, while the New England Journal of Medicine was recognized as the primary journal with the highest total link strength. Keyword co-occurrence analysis revealed significant research topics including "gefitinib", "chemotherapy", "open label", and "erlotinib." Moreover, keyword burst analysis indicated notable periods of increased research focus on topics such as "osimertinib" and "liquid biopsy", suggesting emerging trends and current hotspots in the treatment of EGFR-mutated NSCLC.

This analysis highlights research trends on TKIs for EGFR-mutated NSCLC, emphasizing the importance of targeted therapies like gefitinib and osimertinib for future research and clinical practice enhancement.

Health care system-wide outcomes from routine treatment with erlotinib and gefitinib are incompletely understood.

The aim of the study is to describe the effectiveness of erlotinib and gefitinib during the first decade of their routine use for treating advanced epidermal growth factor receptor (EGFR) mutation-positive nonsquamous non-small cell lung cancer in the entire cohort of patients treated in Aotearoa New Zealand.

Patients were identified, and data collated from national pharmaceutical dispensing, cancer registration, and mortality registration electronic databases by deterministic data linkage using National Health Index numbers. Time-to-treatment discontinuation and overall survival were measured from the date of first dispensing of erlotinib or gefitinib and analyzed by Kaplan-Meier curves. Associations of treatment outcomes with baseline factors were evaluated using univariable and multivariable Cox regressions.

Overall, 752 patients were included who started treatment with erlotinib (n=418) or gefitinib (n=334) before October 2020. Median time-to-treatment discontinuation was 11.6 (95% CI 10.8-12.4) months, and median overall survival was 20.1 (95% CI 18.1-21.6) months. Shorter time-to-treatment discontinuation was independently associated with high socioeconomic deprivation (hazard ratio [HR] 1.3, 95% CI 1.1-1.5 compared to the New Zealand Index of Deprivation 1-4 group), EGFR L858R mutations (HR 1.3, 95% CI 1.1-1.6 compared to exon 19 deletion), and distant disease at cancer diagnosis (HR 1.4, 95% CI 1.2-1.7 compared to localized or regional disease). The same factors were independently associated with shorter overall survival. Outcome estimates and predictors remained unchanged in sensitivity analyses.

Outcomes from routine treatment with erlotinib and gefitinib in New Zealand patients with advanced EGFR-mutant nonsquamous non-small cell lung cancer are comparable with those reported in randomized trials and other health care system-wide retrospective cohort studies. Socioeconomic status, EGFR mutation subtype, and disease extent at cancer diagnosis were independent predictors of treatment outcomes in that setting.

Gray hair, widely regarded as a hallmark of aging. While gray hair is associated with aging, reversing this trait through gene targeting does not alter the fundamental biological processes of aging. Similarly, certain oncogenes (such as CXCR4, MMP-related genes, etc.) can serve as markers of tumor behavior, such as malignancy or prognosis, but targeting these genes alone may not lead to tumor regression. We pioneered the name of this class of genes as "phenotypic genes". Historically, cancer genetics research has focused on tumor driver genes, while genes influencing cancer phenotypes have been relatively overlooked. This review explores the critical distinction between driver genes and phenotypic genes in cancer, using the MAPK and PI3K/AKT/mTOR pathways as key examples. We also discuss current research techniques for identifying driver and phenotypic genes, such as whole-genome sequencing (WGS), RNA sequencing (RNA-seq), RNA interference (RNAi), CRISPR-Cas9, and other genomic screening methods, alongside the concept of synthetic lethality in driver genes. The development of these technologies will help develop personalized treatment strategies and precision medicine based on the characteristics of relevant genes. By addressing the gap in discussions on phenotypic genes, this review significantly contributes to clarifying the roles of driver and phenotypic genes, aiming at advancing the field of targeted cancer therapy.

The macrocyclization of inhibitors has become gradually favored as a new approach for drug design in the field of anticancer agents, since the recent approvals of lorlatinib, pacritinib, and repotrectinib, and feasibility of macrocyclic modification to improve inhibitor drug-like properties has also been confirmed. Macrocycles are receiving increasing attention due to their enhanced binding affinity, target selectivity, and pharmacokinetic properties through conformational constraints. Therefore, this review summarizes various strategies for improving drug-like properties in macrocyclization and structural optimization, and reveals that macrocyclization is a new favorable strategy for drug design, aiming to provide insights for the drug discovery in different targets.

Covalent protein targeting represents a powerful tool for protein characterization, identification, and activity modulation. The safety of covalent therapeutics was questioned for many years due to the possibility of off-target binding and subsequent potential toxicity. Researchers have recently, however, demonstrated many covalent binders as safe, potent, and long-acting therapeutics. Moreover, they have achieved selective targeting among proteins with high structural similarities, overcome mutation-induced resistance, and obtained higher potency compared to non-covalent binders. In this review, we highlight the different classes of binding sites on a target protein that could be addressed by a covalent binder. Upon folding, proteins generate various concavities available for covalent modifications. Selective targeting to a specific site is driven by differences in the geometry and physicochemical properties of the binding pocket residues as well as the geometry and reactivity of the covalent modifier "warhead". According to the warhead reactivity and the nature of the binding region, covalent binders can alter or lock a targeted protein conformation and inhibit or enhance its activity. We survey these various modification sites using case studies of recently discovered covalent binders, bringing to the fore the versatile application of covalent protein binders with respect to drug discovery approaches.

Dysregulation of epidermal growth factor receptor (EGFR) is one of the most common mechanisms associated with the pathogenesis of various cancers. Mitogen-inducible gene 6 [MIG6; also known as ERBB receptor feedback inhibitor 1 (ERRFI1)], identified as a feedback inhibitor of EGFR, negatively regulates EGFR by directly inhibiting its kinase activity and facilitating its internalization, subsequently leading to degradation. Despite its proposed role as an EGFR-dependent tumor suppressor, the functional consequences and clinical relevance in cancer etiology remain incompletely understood. Here, we identify that the stoichiometric balance between MIG6 and EGFR is crucial in promoting EGFR-dependent oncogenic growth in various experimental model systems. In addition, a subset of ERRFI1 (the official gene symbol of MIG6) mutations exhibit impaired ability to suppress the enzymatic activation of EGFR at multiple levels. In summary, our data suggest that decreased or loss of MIG6 activity can lead to abnormal activation of EGFR, potentially contributing to cellular transformation. We propose that the mutation status of ERRFI1 and the expression levels of MIG6 can serve as additional biomarkers for guiding EGFR-targeted cancer therapies, including glioblastoma.

This study investigated the relationship between E-cadherin down-regulation and enhanced pERK1/2 signaling in cervical cancer, evaluated their combined prognostic impact, and explored potential therapeutic targets.

We analyzed 188 cervical cancer specimens and 300 normal cervical tissue samples using tissue microarray and immunohistochemistry. Small interfering RNA transfection and western blotting were used to study molecular interactions in cervical cancer cell lines.

We observed a significant inverse correlation between E-cadherin and pERK1/2 expression, as well as poor disease-free survival and overall survival. Additionally, molecular analysis indicated that E-cadherin silencing enhanced ERK signaling and promoted cancer cell proliferation.

The findings suggest that E-cadherin and pERK1/2 are crucial biomarkers for cervical cancer prognosis and their interaction provides a potential target for therapeutic interventions. Further studies are recommended to explore these pathways in the clinical setting.

This review comprehensively analyzes the current landscape of tumor-agnostic therapies in oncology. Tumor-agnostic therapies are designed to target specific molecular alterations rather than the primary site of the tumor, representing a shift in cancer treatment. We discuss recent approvals by regulatory agencies such as the FDA and EMA, highlighting therapies that have demonstrated efficacy across multiple cancer types sharing common alterations. We delve into the trial methodologies that underpin these approvals, emphasizing innovative designs such as basket trials and umbrella trials. These methodologies present unique advantages, including increased efficiency in patient recruitment and the ability to assess drug efficacy in diverse populations rapidly. However, they also entail certain challenges, including the need for robust biomarkers and the complexities of regulatory requirements. Moreover, we examine the promising prospects for developing therapies for rare cancers that exhibit common molecular targets typically associated with more prevalent malignancies. By synthesizing these insights, this review underscores the transformative potential of tumor-agnostic therapies in oncology. It offers a pathway for personalized cancer treatment that transcends conventional histology-based classification.

Lung cancer often causes bone metastasis, and denosumab is administered to bone metastases to prevent bone-related adverse events. One of the important side effects of denosumab is hypocalcemia, but this is generally not a problem, as it is used with calcium supplementation. A 48-year-old non-smoker male was diagnosed with lung adenocarcinoma with EGFR L858R mutation with diffuse bone metastases. Three days after receiving denosumab, the patient developed weakness and numbness in his limbs and was diagnosed with drug-induced hypocalcemia due to denosumab. It takes more than 4 months for treating the hypocalcemia in this case with continuous intravenous infusion of calcium gluconate with oral calcium supplementation for 2 months of hospitalization and subsequent 2 months of outpatient treatment with intermittent intravenous infusion of calcium gluconate three times a week along with oral supplementation. Tartrate-resistant acid phosphatase-5b (TRACP-5b), a marker of bone resorption, was a biomarker for the required amount of calcium in this case. Patients with lung cancer with diffuse osteoblastic bone metastases could develop severe hypocalcemia and require long-term calcium supplementation.

Osimertinib combined with chest radiotherapy has a high incidence of pneumonia, dacomitinib is widely used in clinical practice, but there are no studies reporting the pulmonary safety of dacomitinib in combinating with radiotherapy. Here we report a case of radiation pneumonitis occurring by dacomitinib and thoracic radiotherapy (TRT). The patient was a 55-year-old woman with lung adenocarcinoma. She had received surgery and adjuvant chemotherapy. The patient presented with bilateral intramammary and para-aortic metastatic lymphadenopathy, which was confirmed as metastasis, and subsequently received treatment with dacomitinib. Radiotherapy started after 4 months of dacomitinib. The Clinical Target Volume (CTV) was metastatic lymph nodes area. The prescription dose was 60 Gy/30F. The mean lung dose (MLD), V20, and V5 were 8.16Gy, 16%, and 34.5%. Despite the lung V20 and mean lung dose being exceptionally low, the patient exhibited respiratory symptoms, and a CT chest scan revealed grade 4 radiation pneumonitis two weeks following the conclusion of radiotherapy. The radiotherapy and dacomitinib were discontinued, and immediate initiation of pulmonary anti-inflammatory treatment ensued. The concurrent administration of dacomitinib and RT carries the risk of inducing serious pneumonia. This case highlights the potential risk of severe pneumonia associated with this combination therapy, emphasizing the need for further research to clarify its safety and develop effective management strategies.

Mutations in human receptor tyrosine kinase epidermal growth factor receptor-2 (HER2) are rare. This study aimed to investigate the clinical characteristics and computed tomography (CT) texture features of lung adenocarcinoma (LUAD) patients with HER2 mutation.

This study included 933 LUAD patients from January 2018 to December 2023 and classified their CT textures accordingly.

The data indicated that the incidence of HER2 mutation was higher in younger LUAD patients than in elder patients [7.5% (31/413) vs. 1.5% (8/520), p < 0.0001] and was associated with never-smokers [0% (0/78) vs. 4.6% (39/855), p = 0.03]. In this study, the tumors were categorized based on their diameter into T1a and ≥ T1b. The data revealed that HER2 mutation was more frequent in T1a than in ≥ T1b [11.0% (23/210) vs. 2.2% (16/723), p < 0.0001]. Furthermore, non-pSD was more common than pSD in LUAD with HER2 mutation than in LUAD with HER2 wild type [82.1% (31/39) vs.17.9% (7/39), p = 0.01]. Moreover, the size of pGGO (0.94 ± 0.29 cm vs. 1.24 ± 0.39 cm, p = 0.0009), mGGO (0.86 ± 0.39 cm vs. 1.5 ± 0.77 cm, p < 0.0001) and pSD (1.75 ± 0.81 cm vs. 2.5 ± 1.4 cm, p < 0.05) in LUAD patients with HER2 mutation was smaller than those with HER2 wild type patients. In addition, when LUADs with HER2 wild type transformed from pGGO to mGGO, their sizes increased significantly (1.50 ± 0.77 cm vs. 1.24 ± 0.39 cm). It was also observed that the incidence of LUAD with HER2 mutation of ≤ 1 cm was significantly more than that of > 1 cm comparing to that in LUAD with HER2 wild type [14.8% (12/81) vs. 1.7% (3/173), p < 0.0001].

This study indicated that the incidence of HER2 mutation was higher in younger and never-smoking LUAD patients. Furthermore, the growth of LUAD with HER2 mutation was slower than that of those with HER2 wild type. Moreover, most LUAD with HER2 mutation changed into pSD after > 1 cm.

Over the past decades, significant progress has been made in the understanding of non-small cell lung cancer (NSCLC) biology and tumor progression mechanisms, resulting in the development of novel strategies for early detection and wide-ranging care approaches. Since their introduction, over 20 years ago, targeted therapies with tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for NSCLC. Nowadays, targeted therapies remain the gold standard for many patients, but still they suffer from many adverse effects, including unexpected toxicity and intrinsic acquired resistance mutations, which lead to relapse. The adoption of immune checkpoint inhibitors (ICIs) in 2015, has offered exceptional survival benefits for patients without targetable alterations. Despite this notable progress, challenges remain, as not all patients respond favorably to ICIs, and resistance to therapy can develop over time. A crucial factor influencing clinical response to immunotherapy is the tumor microenvironment (TME). The TME is pivotal in orchestrating the interactions between neoplastic cells and the immune system, influencing tumor growth and treatment outcomes. In this review, we discuss how the understanding of this intricate relationship is crucial for the success of immunotherapy and survey the current state of immunotherapy intervention, with a focus on forthcoming and promising chimeric antigen receptor (CAR) T cell therapies in NSCLC. The TME sets major obstacles for CAR-T therapies, creating conditions that suppress the immune response, inducing T cell exhaustion. To enhance treatment efficacy, specific efforts associated with CAR-T cell therapy in NSCLC, should definitely focus TME-related immunosuppression and antigen escape mechanisms, by combining CAR-T cells with immune checkpoint blockades.

The combination of PD-1/PD-L1 inhibitor with CTLA-4 inhibitor for advanced non-small cell lung cancer(NSCLC) is presently a significant area of research, however its clinical application remains contentious. This meta-analysis aimed to assess the efficacy and safety of first-line PD-1/PD-L1 inhibitor in combination with CTLA-4 inhibitor (CP) in the treatment of patients with advanced NSCLC.

A systemic search was conducted in four databases (PubMed, Cochrane library, Embase, and Web of Science) from their establishment until January 17, 2024, for randomized controlled trials that investigated the use of the first-line PD-1/PD-L1 inhibitor plus CTLA-4 inhibitor in patients with advanced NSCLC. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were subjected to meta-analyses.

Totally 7 eligible randomized controlled trials including 4682 people were included. Two comparative analyses were performed: CP versus chemotherapy, CP versus PD-1/PD-L1 inhibitor (P). Compared with the chemotherapy group, CP improved OS (HR: 0.84, 95% CI: 0.75-0.94, p<0.05) but not PFS (HR: 0.94, 95%CI: 0.73-1.20, p = 0.63) or ORR (OR: 1.16, 95% CI: 0.79-1.71, p = 0.45). In terms of toxicity, CP had slightly fewer any AEs compared to chemotherapy (RR: 0.94, 95% CI: 0.91-0.97; p<0.05). Compared to the P group, there was no significant difference in OS (MD: -0,25, 95% CI: -2.47-1.98, p = 0.83), PFS (MD: -0.91, 95% CI: -3.19-1.36, p = 0.43), and ORR (OR:1.05, 95% CI. 0.80-1.36, p = 0.73). Subgroup analysis revealed that CP provided superior OS compared with P in patients with PD-L1 expression < 1%.

CP was a feasible and safe first-line therapy for patients with advanced NSCLC. Specifically, CP may function as a therapeutic alternative for individuals with low or negative PD-L1 expression, resulting in enhanced long-term outcomes compared to chemotherapy or P. Further randomized controlled trials with prolonged follow-up periods are necessary to validate these results, particularly focusing on efficacy in patients with differing PD-L1 expression levels, to improve the stratified implementation of immunotherapy.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024621116, identifier CRD42024621116.

Determining mutations in the kinase domain of the epidermal growth factor receptor (EGFR) is critical for the effectiveness of EGFR tyrosine kinase inhibitors (TKIs) in lung cancer. Yet, DNA-based sequencing analysis of tumor samples is time-consuming and only provides gene mutation information on EGFR, making it challenging to design effective EGFR-TKI therapeutic strategies. Here, we present a new image-based method involving the rational design of a quenched probe based on EGFR-TKI to identify mutant proteins, which permits specific and "no-wash" real-time imaging of EGFR in living cells only upon covalent targeting of the EGFR kinase. We also show that the probe enables distinguishing EGFR mutant tumor-bearing mice from wild-type tumor-bearing mice via fluorescence-intensity-based imaging with high signal contrast. More interestingly, the image-based phenotypic approach can be used to predict EGFR mutations in tumors from lung cancer patients with an accuracy of 94%. Notably, when immunohistochemistry analysis is integrated, an improved accuracy of 98% is achieved. These data delineate a drug-based phenotypic imaging approach for in-biopsy visualization and define functional groups of EGFR mutants that can effectively guide EGFR-TKI therapeutic decision-making besides gene mutation analysis.

Chromosome engineering is a transformative field at the cutting edge of biological science, offering unprecedented precision in manipulating large-scale genomic DNA within cells. This discipline is central to deciphering how the multifaceted roles of chromosomes-guarding genetic information, encoding sequence positional information, and influencing organismal traits-shape the genetic blueprint of life. This review comprehensively examines the technological advancements in chromosome engineering, which center on engineering chromosomal rearrangements, generating artificial chromosomes, de novo synthesizing chromosomes, and transferring chromosomes. Additionally, we introduce the application progress of chromosome engineering in basic and applied research fields, showcasing its capacity to deepen our knowledge of genetics and catalyze breakthroughs in therapeutic strategies. Finally, we conclude with a discussion of the challenges the field faces and highlight the profound implications that chromosome engineering holds for the future of modern biology and medical applications.

Treatment landscape in metastatic lung cancer has progressed quickly over the last decade, mainly due to immunotherapies and targeted therapies. This study aimed to describe change in epidemiological data of patients with metastatic lung cancer.

A cohort of patients identified between 2013 and 2021 with lung cancer and a marker of metastases (ICD-10 code or reimbursement for Bevacizumab or Pemetrexed) was built from the French claims database. A trend analysis of the rate of newly-diagnosed metastatic patients and the proportion of deaths over the study period was performed using Joinpoint® software.

Between 2013 and 2021, 147,760 metastatic lung cancer patients were identified (men: 66.5%, median age: 66 years). A statistically significant decrease in the crude rate of newly-diagnosed metastatic patients was observed in men (-1.18% per year in average), whereas a statistically significant increase was described in women (+2.36% per year in average). A downward trend in the proportion of deaths was found for both gender (-4.37% and -5.07% per year on average, respectively).

This study provides unpublished epidemiological data on metastatic lung cancer in France and confirms sex-differentiated trends in the rate of newly-diagnosed metastatic patients, already observed for all stages combined. A statistically significant decrease in the proportion of deaths among metastatic lung cancer patients is observed in both genders. These results underline the importance of ongoing investments in prevention and screening initiatives to reverse the incidence trends observed in women. Moreover, it highlights the criticality of therapeutic innovation in sustaining the increase in survival.

The epidermal growth factor receptor (EGFR) has been extensively studied for its critical role in the development and progression of various malignancies. In this comprehensive pan-cancer analysis, we investigated the potential of EGFR as a biomarker across multiple tumor types; a comprehensive analysis of EGFR gene mutation and copy number variation was conducted using cBioPortal and other tools. Utilizing multi-omics datasets from The Cancer Genome Atlas (TCGA), we analyzed EGFR's expression patterns, prognostic implications, genetic mutations, and molecular interactions in different cancers. Our findings revealed frequent dysregulation of EGFR in several tumor types, including lung cancers and glioblastoma multiforme. High EGFR expression was consistently associated with poor clinical outcomes, such as reduced overall survival, disease-free survival, and progression-free survival. Genetic alteration analysis indicated a high frequency of EGFR mutations and copy number variations, particularly in glioblastoma multiforme. Additionally, our study suggests a complex relationship between EGFR expression and cancer-associated fibroblast infiltration, which may contribute to an immunosuppressive tumor microenvironment. These findings underscore the clinical relevance of EGFR as a prognostic biomarker and therapeutic target, emphasizing the need for further research and the development of targeted therapies to enhance patient outcomes in cancers with EGFR alterations. The co-expression network of EGFR with genes and proteins involved in cell cycle regulation and mitotic control provided insights into the molecular mechanisms of oncogenesis.

To investigate the diagnostic value of high-resolution melting (HRM) analysis for oncology-associated epidermal growth factor receptor (EGFR) gene mutations.

We systematically searched Embase, PubMed, and Web of Science for HRM and EGFR mutation detection studies published through September 2024. True and false positives and negatives were extracted to evaluate the diagnostic accuracy of HRM to detect EGFR mutations. The study was registered at INPLASY (INPLASY202490062).

Twenty-six articles were obtained from 416 references. The overall diagnostic sensitivity and specificity were high at 0.95 [95% confidence interval (CI), 0.94-0.96] and 0.99 (95% CI, 0.99-0.99), respectively. Other indicators, including the positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio, were 144.91 (95% CI: 69.07-304.04), 0.08 (95% CI: 0.04-0.13), and 2405.21 (95% CI: 1231.87-4696.13), respectively. The Q value of the summary receiver operating characteristic curve was 0.979, and the area under the curve was 0.997.

As a pre-screening method, the high specificity, sensitivity, low cost, rapid turnaround, and simplicity of HRM make it a good alternative for clinical practice, but positive results must still be obtained for diagnostic confirmation. This study provides a transparent overview of relevant studies in design and conduct.

The discovery of the association between EGFR mutations and the efficacy of EGFR tyrosine-kinase inhibitors (TKIs) has revolutionized the treatment paradigm for patients with non-small-cell lung cancer (NSCLC). Currently, third-generation EGFR TKIs, which are often characterized by potent central nervous system penetrance, are the standard-of-care first-line treatment for advanced-stage EGFR-mutant NSCLC. Rational combinations of third-generation EGFR TKIs with anti-angiogenic drugs, chemotherapy, the EGFR-MET bispecific antibody amivantamab or local tumour ablation are being investigated as strategies to delay drug resistance and increase clinical benefit. Furthermore, EGFR TKIs are being evaluated in patients with early stage or locally advanced EGFR-mutant NSCLC, with the ambitious aim of achieving cancer cure. Despite the inevitable challenge of acquired resistance, emerging treatments such as new TKIs, antibody-drug conjugates, new immunotherapeutic approaches and targeted protein degraders have shown considerable promise in patients with progression of EGFR-mutant NSCLC on or after treatment with EGFR TKIs. In this Review, we describe the current first-line treatment options for EGFR-mutant NSCLC, provide an overview of the mechanisms of acquired resistance to third-generation EGFR TKIs and explore novel promising treatment strategies. We also highlight potential avenues for future research that are aimed at improving the survival outcomes of patients with this disease.

The epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) has a unique "cold" immune profile. DNA damage repair (DDR) genes are closely related to tumorigenesis and the effectiveness of immunotherapy in many tumors. However, the role and mechanism of DDR in the genesis and progression of EGFRm NSCLC remain unclear.

This study included 101 EGFRm NSCLC samples from The Cancer Genome Atlas (TCGA) dataset and a GSE31210 dataset (external set) from the GEO database. Cluster analysis was used to identify different subtypes of EGFRm NSCLC based on the expression of DDR genes. Univariate and LASSO regression analysis was used to develop a DDR-based predictive model. The prognostic significance of this model was assessed using Cox regression, Kaplan-Meier, and receiver operating characteristic (ROC) curve analyses. Bioinformatics analysis was performed to investigate the clinicopathological characteristics and immune profiles associated with this model. In vitro experiment was performed to testify the role of DDR genes in EGFRm NSCLC.

We identified two subtypes of EGFRm NSCLC: DDR-activated and DDR-suppressed. The DDR-activated subtype showed more aggressive clinical behavior and poorer prognosis and was more responsive to immunotherapy. A prognostic model for EGFRm NSCLC was constructed using four DDR genes: CAPS, FAM83A, IGLV8-61, and SLC7A5. The derived risk score could serve as an independent prognostic indicator. High- and low-risk patients exhibited distinct clinicopathological characteristics, immune profiles, and responses to immunotherapy. The T-cell inflammation and Tumor Immune Dysfunction and Exclusion (TIDE) scores differed between the high- and low-risk subgroups, with both showing enhanced effectiveness of immunotherapy in the low-risk subgroup. Targeted therapy such as BI.2536, an inhibitor of polo-like kinase 1, could be effective for patients with high-risk EGFRm NSCLC. Meanwhile, in vitro detection approved the role of DDR genes in EGFRm NSCLC response.

This study demonstrated a diversity of DDR genes in EGFRm NSCLC and developed a predictive model using these genes. This model could assist in identifying potential candidates for immunotherapy and in assessing personalized treatment and prognosis of patients with EGFRm NSCLC.

We explored the rationale for treating glioblastoma (GBM) with regorafenib. In 103 newly diagnosed GBM patients, we assessed mutations, copy number variants (CNVs), fusions, and overexpression in 46 genes encoding protein kinases (PKs) potentially targeted by regorafenib or its metabolites and performed a functional enrichment analysis to assess their implications in angiogenesis. We analyzed regorafenib's binding inhibitory activity and target affinity for these 46 PKs and focused on a subset of 18 genes inhibited by regorafenib at clinically achievable concentrations and on 19 genes involved in angiogenesis. Putative oncogenic alterations were defined as oncogenic/likely oncogenic mutations, oncogenic fusions, CNVs > 5, and/or gene overexpression. Regorafenib did not target all 46 PKs. For the 46-gene set, 40 genes (86.9%) and 73 patients (70.8%) harbored at least one alteration in genes encoding targetable PKs, but putative oncogenic alterations were present in only 34 patients (33%). In the 18-gene set, 18 genes (100%) and 48 patients (46.6%) harbored alterations, but putative oncogenic alterations were detected in only 26 patients (25.2%). Thirty patients (29.1%) had oncogenic alterations in the 18-gene set and/or in angiogenesis-related genes. Around 33% of patients had oncogenic alterations in any of the 46 potential targets. Additionally, the suboptimal dosing of regorafenib, due to its poor penetration of the blood-brain barrier, may reduce the likelihood of effectively targeting certain PKs. Future use of multi-target drugs must be guided by a thorough understanding of target presence, effective inhibition, and the drug's ability to reach brain tumors at adequate concentrations.

Background: Lung cancer remains the leading cause of cancer mortality globally with EGFR mutations representing a significant driver in advanced non-small cell lung cancer (aNSCLC). The timely detection of these mutations is critical for initiating targeted therapy, yet tissue biopsy limitations often delay treatment. Methods: This multicenter prospective study evaluated the clinical utility of liquid biopsy (LBx) in real-life settings for the early diagnosis of EGFR mutations in patients with suspected aNSCLC. Circulating tumor DNA (ctDNA) was analyzed using the Cobas EGFR Mutation Test and compared to tissue-based next-generation sequencing (NGS). Results: Among 366 aNSCLC patients tested, LBx demonstrated a significantly shorter median turnaround time (TAT) of 3 days compared to 26 days for tissue NGS (p < 0.001) with 100% specificity and 65% sensitivity for EGFR mutation detection. LBx identified actionable EGFR mutations in cases where tissue biopsy was insufficient or unavailable, enabling 43.7% of patients to commence targeted therapy based on ctDNA results prior to biopsy confirmation. Conclusions: These findings highlight the potential of LBx to reduce diagnostic delays and improve access to personalized therapies in a real-world setting. Integrating LBx into routine diagnostic workflows may address current gaps in molecular testing, ensuring timely and precise treatment for aNSCLC patients.

The epidermal growth factor receptor (EGFR) regulates gene expression through two primary mechanisms: as a growth factor in the nucleus, where it translocates upon binding its ligand, or via its intrinsic tyrosine kinase activity in the cytosol, where it modulates key signaling pathways such as RAS/MYC, PI3K, PLCγ, and STAT3. During tumorigenesis, these pathways become deregulated, leading to uncontrolled proliferation, enhanced migratory and metastatic capabilities, evasion of programmed cell death, and resistance to chemotherapy or radiotherapy. The RAS and MYC oncogenes are pivotal in tumorigenesis, driving processes such as resistance to apoptosis, replicative immortality, cellular invasion and metastasis, and metabolic reprogramming. These oncogenes are subject to regulation by a range of epigenetic and post-transcriptional modifications. This review focuses on the deregulation of EGFR, RAS, and MYC expression caused by (epi)genetic alterations and post-translational modifications. It also explores the therapeutic potential of targeting these regulatory proteins, emphasizing the importance of phenotyping neoplastic tissues to inform the treatment of cancer.

Recently there has been an increasing number of studies have explored apoptosis mechanisms in lung cancer (LC). However, no researchers have conducted a bibliometric analysis of the most cited articles in this field.

To examine the top 100 most influential and cited publications on apoptosis in non-small cell lung cancer (NSCLC) from 2004 to 2023, summarizing research trends and key focus areas.

This study utilized the Web of Science Core Database (WOSCC) to research NSCLC apoptosis from 2004 to 2023, using keyword selection and manual screening for article searches. Bibliometrix package of R software 4.3.1 was used to generate distribution statistics for the top ten institutions, journals and authors. Citespace6.2. R6 was used to create the visualization maps for keyword co-occurrence and clustering. VOSviewer1.6.19 was used to conduct cluster analysis of publishing countries (regions), with data exported to SCImago Graphica for geographic visualization and cooperation analysis. VOSviewer1.6.19 was used to produced co-citation maps of institutions, journals, authors, and references.

From 2004 to 2023, 13316 articles were retrieved, and the top 100 most cited were chosen. These were authored by 934 individuals from 269 institutions across 18 countries and appeared in 45 journals. Citations ranged from 150 to 1,389, with a median of 209.5. The most influential articles appeared in 2005 and 2007 (n=13). The leading countries (regions), institutions, journals and authors were identified as the United States (n=60), Harvard University (n=64), CANCER RESEARCH (n=15), SUN M and YANG JS (n=6). The top five keywords were "expression", "activation", "apoptosis", "pathway" and "gefitinib". This study indicates that enhancing apoptosis through circular RNA regulation and targeting the Nrf2 signaling pathway could become a key research focus in recent years.

Apoptosis has been the subject of extensive research over many years, particularly in relation to its role in the pathogenesis, diagnosis, and treatment of NSCLC. This study aims to identify highly influential articles and forecast emerging research trends, thereby offering insights into novel therapeutic targets and strategies to overcome drug resistance. The findings are intended to serve as a valuable reference for scholars engaged in this field of study.