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Récepteurs ErbB , Tumeurs du poumon , Mutation , Humains , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/thérapie , Récepteurs ErbB/génétique , Stadification tumorale , Norme de soins , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/thérapieRÉSUMÉ
BACKGROUND: This study details a case of a patient with advanced lung adenocarcinoma harboring an exon 19 deletion in the EGFR gene. METHOD: A 46-year-old female patient was diagnosed with stage IVb left lung adenocarcinoma, with multiple bone and lymph node metastases. Following the identification of tumor-specific antigen peptides, the patient received a combination treatment of immunotherapy (TSA-DC-CTL) and oral osimertinib. Peripheral blood circulating immune cells and circulating tumor cells (CTCs) were monitored before and after treatment. PET-CT and CT scans were used to assess the tumor response to treatment. RESULTS: A significant increase in total lymphocyte percentage and decrease in the number of CTCs in the patient was observed. Imaging studies showed a notable reduction in tumor metastases. CONCLUSION: This report demonstrates the safety and efficacy of TSA-DC-CTL cell immunotherapy combined with osimertinib in the treatment of a patient with advanced lung adenocarcinoma with an EGFR exon 19 deletions. This study describes a promising new treatment option for patients with advanced lung cancer with EGFR mutations.
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Acrylamides , Adénocarcinome pulmonaire , Dérivés de l'aniline , Récepteurs ErbB , Tumeurs du poumon , Mutation , Humains , Acrylamides/usage thérapeutique , Dérivés de l'aniline/usage thérapeutique , Dérivés de l'aniline/pharmacologie , Femelle , Récepteurs ErbB/génétique , Adulte d'âge moyen , Adénocarcinome pulmonaire/génétique , Adénocarcinome pulmonaire/traitement médicamenteux , Adénocarcinome pulmonaire/thérapie , Adénocarcinome pulmonaire/anatomopathologie , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/thérapie , Immunothérapie/méthodes , Association thérapeutique , Résultat thérapeutique , Indoles , PyrimidinesRÉSUMÉ
Cobas EGFR mutation Test v2 was FDA-approved as qualitative liquid biopsy for actionable EGFR variants in non-small cell lung cancer (NSCLC). It generates semiquantitative index (SQI) values that correlate with mutant allele levels, but decision thresholds for clinical use in NSCLC surveillance are lacking. We conducted long-term ctDNA monitoring in 20 subjects with EGFR-mutated NSCLC; resulting in a 155 on-treatment samples. We defined optimal SQI intervals to predict/rule-out progression within 12 weeks from sampling and performed orthogonal calibration versus deep-sequencing and digital PCR. SQI showed significant diagnostic power (AUC 0.848, 95% CI 0.782-0.901). SQI below 5 (63% of samples) had 93% (95% CI 87-96%) NPV, while SQI above 10 (25% of samples) had 69% (95% CI 56-80%) PPV. Cobas EGFR showed perfect agreement with sequencing (Kappa 0.860; 95% CI 0.674-1.00) and digital PCR. SQI values strongly (r: 0.910, 95% 0.821-0.956) correlated to mutant allele concentrations with SQI of 5 and 10 corresponding to 6-9 (0.2-0.3%) and 64-105 (1.1-1.6%) mutant allele copies/mL (VAF) respectively. Our dual-threshold classifier of SQI 0/5/10 yielded informative results in 88% of blood draws with high NPV and good overall clinical utility for patient-centric surveillance of metastatic NSCLC.
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Carcinome pulmonaire non à petites cellules , Récepteurs ErbB , Tumeurs du poumon , Mutation , Humains , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/anatomopathologie , Récepteurs ErbB/génétique , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Mâle , Femelle , Adulte d'âge moyen , Sujet âgé , Biopsie liquide/méthodes , ADN tumoral circulant/génétique , ADN tumoral circulant/sang , Analyse de mutations d'ADN/méthodes , Métastase tumoraleRÉSUMÉ
In EGFR-mutated lung cancer, the duration of response to tyrosine kinase inhibitors (TKIs) is limited by the development of acquired drug resistance. Despite the crucial role played by apoptosis-related genes in tumor cell survival, how their expression changes as resistance to EGFR-TKIs emerges remains unclear. Here, we conduct a comprehensive analysis of apoptosis-related genes, including BCL-2 and IAP family members, using single-cell RNA sequence (scRNA-seq) and spatial transcriptomics (ST). scRNA-seq of EGFR-mutated lung cancer cell lines captures changes in apoptosis-related gene expression following EGFR-TKI treatment, most notably BCL2L1 upregulation. scRNA-seq of EGFR-mutated lung cancer patient samples also reveals high BCL2L1 expression, specifically in tumor cells, while MCL1 expression is lower in tumors compared to non-tumor cells. ST analysis of specimens from transgenic mice with EGFR-driven lung cancer indicates spatial heterogeneity of tumors and corroborates scRNA-seq findings. Genetic ablation and pharmacological inhibition of BCL2L1/BCL-XL overcome or delay EGFR-TKI resistance. Overall, our findings indicate that BCL2L1/BCL-XL expression is important for tumor cell survival as EGFR-TKI resistance emerges.
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Apoptose , Récepteurs ErbB , Tumeurs du poumon , Mutation , Analyse sur cellule unique , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/métabolisme , Tumeurs du poumon/traitement médicamenteux , Récepteurs ErbB/métabolisme , Récepteurs ErbB/génétique , Humains , Apoptose/génétique , Apoptose/effets des médicaments et des substances chimiques , Animaux , Souris , Mutation/génétique , Régulation de l'expression des gènes tumoraux , Lignée cellulaire tumorale , RNA-Seq , Transcriptome/génétique , Résistance aux médicaments antinéoplasiques/génétique , Inhibiteurs de protéines kinases/pharmacologie , Souris transgéniques , Analyse de profil d'expression de gènes , Protéine bcl-X/métabolisme , Protéine bcl-X/génétique , Analyse de l'expression du gène de la cellule uniqueRÉSUMÉ
INTRODUCTION: This retrospective study aimed to investigate treatment patterns and outcomes in patients with NSCLC harboring EGFR20ins in China. EGFR20ins mutations are associated with poor responses to EGFR-TKIs, and limited real-world data exist regarding the efficacy of various treatment modalities. METHODS: In this retrospective, single-center study, treatment outcomes, including PFS and ORR, were evaluated for different treatment regimens based on imaging assessments. The impact of mutation heterogeneity on treatment efficacy was also explored. RESULTS: Data from 302 patients diagnosed with NSCLC with EGFR20ins were analyzed. EGFR-TKI monotherapy demonstrated suboptimal PFS compared to platinum-based chemotherapy in the first-line setting (3.00 m vs. 6.83 m, HR = 3.674, 95%CI = 2.48-5.44, p < 0.001). Platinum plus pemetrexed plus bevacizumab combination therapy showed improved PFS and ORR compared to platinum plus pemetrexed (7.50m vs. 5.43 m, HR = 0.593, 95%CI = 0.383-0.918, p = 0.019). In later-line treatments, monotherapy with EGFR-TKIs or ICIs exhibited suboptimal efficacy. The specific EGFR20ins subtype, A763_Y764insFQEA, showed favorable responses to EGFR-TKIs in real-world settings. CONCLUSIONS: This large-scale real-world study provides valuable insights into the treatment patterns and outcomes of NSCLC patients with EGFR20ins mutations in China. These findings contribute to the understanding of EGFR20ins treatment and provide real-world benchmark for future clinical trials and drug development.
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Protocoles de polychimiothérapie antinéoplasique , Carcinome pulmonaire non à petites cellules , Récepteurs ErbB , Exons , Tumeurs du poumon , Humains , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/anatomopathologie , Mâle , Femelle , Récepteurs ErbB/génétique , Tumeurs du poumon/génétique , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/anatomopathologie , Adulte d'âge moyen , Études rétrospectives , Sujet âgé , Chine , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Résultat thérapeutique , Adulte , Pémétrexed/usage thérapeutique , Pémétrexed/administration et posologie , Inhibiteurs de protéines kinases/usage thérapeutique , Mutagenèse par insertion , Mutation , Sujet âgé de 80 ans ou plus , Peuples d'Asie de l'EstSujet(s)
Acrylamides , Adénocarcinome pulmonaire , Afatinib , Dérivés de l'aniline , Résistance aux médicaments antinéoplasiques , Récepteurs ErbB , Exons , Tumeurs du poumon , Mutation , Humains , Récepteurs ErbB/génétique , Afatinib/usage thérapeutique , Afatinib/pharmacologie , Acrylamides/usage thérapeutique , Acrylamides/pharmacologie , Mutation/génétique , Résistance aux médicaments antinéoplasiques/génétique , Tumeurs du poumon/génétique , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/anatomopathologie , Adénocarcinome pulmonaire/génétique , Adénocarcinome pulmonaire/traitement médicamenteux , Adénocarcinome pulmonaire/anatomopathologie , Dérivés de l'aniline/usage thérapeutique , Dérivés de l'aniline/pharmacologie , Exons/génétique , Femelle , Pipérazines/usage thérapeutique , Pipérazines/pharmacologie , Mâle , Indoles , PyrimidinesSujet(s)
Acrylamides , Dérivés de l'aniline , Antinéoplasiques , Carcinome pulmonaire non à petites cellules , Récepteurs ErbB , Tumeurs du poumon , Mutation , Humains , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/génétique , Acrylamides/usage thérapeutique , Tumeurs du poumon/génétique , Tumeurs du poumon/traitement médicamenteux , Récepteurs ErbB/génétique , Dérivés de l'aniline/usage thérapeutique , Antinéoplasiques/usage thérapeutique , Pipérazines/usage thérapeutique , Stadification tumorale , Inhibiteurs de protéines kinases/usage thérapeutique , Indoles , PyrimidinesRÉSUMÉ
EGFR mutations are critical oncogenic drivers in lung adenocarcinoma (LUAD). However, the mechanisms by which they impact the tumor microenvironment (TME) and tumor immunity are unclear. Furthermore, the reasons underlying the poor response of EGFR-mutant (EGFR-MU) LUADs to immunotherapy with PD-1/PD-L1 inhibitors are unknown. Utilizing single-cell RNA (sc-RNA) and bulk RNA sequencing datasets, we conducted high-dimensional weighted gene coexpression network analysis to identify key genes and immune-related pathways contributing to the immunosuppressive TME. EGFR-MU cancer cells downregulated MHC class I genes to evade CD8+ cytotoxic T cells, expressed substantial levels of MHC class II molecules, and engaged with CD4+ regulatory T cells (Tregs). EGFR-MU tumors may recruit Tregs primarily through the CCL17/CCL22/CCR4 axis, leading to a Treg-enriched TME. High levels of MHC class II-positive cancer-associated fibroblasts and tumor endothelial cells were found within EGFR-MU tumors. Owing to the absence of costimulatory factors, they may inhibit rather than activate the tumor antigen-specific CD4+ T-cell response, contributing further to immune suppression. Multiplex immunohistochemistry analyses in a LUAD cohort confirmed increased expression of MHC class II molecules in cancer cells and fibroblasts in EGFR-MU tumors. Our research elucidates the highly immunosuppressive TME in EGFR-MU LUAD and suggests potential targets for effective immunotherapy.
Sujet(s)
Récepteurs ErbB , Analyse de profil d'expression de gènes , Tumeurs du poumon , Mutation , Microenvironnement tumoral , Humains , Récepteurs ErbB/génétique , Récepteurs ErbB/métabolisme , Tumeurs du poumon/génétique , Tumeurs du poumon/immunologie , Tumeurs du poumon/anatomopathologie , Microenvironnement tumoral/immunologie , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/métabolisme , Régulation de l'expression des gènes tumoraux , Adénocarcinome pulmonaire/génétique , Adénocarcinome pulmonaire/immunologie , Adénocarcinome pulmonaire/anatomopathologie , Transcriptome , Analyse sur cellule uniqueRÉSUMÉ
Catalpol, a natural iridoid glycoside, has potential therapeutic benefits, including anti-inflammatory and neuroprotective effects. Investigating catalpol's role in angiogenesis is critical for understanding its potential therapeutic applications, particularly in diseases where modulating angiogenesis is beneficial. This study investigates catalpol's influence on angiogenesis and its mechanisms, combining network pharmacology and in vitro experiments. The target genes corresponding to the catalpol were analyzed by SwissTargetPrediction. Then angiogenesis-related targets were acquired from databases like GeneCards. Subsequently, the Database for Annotation, Visualization and Integrated Discovery was employed for Gene Ontology and pathway analysis, while Cytoscape visualized protein interactions. The effect of catalpol on viability and angiogenesis of HUVECs was further examined using Cell Counting Kit-8 and angiogenesis assays. RT-qPCR and western blot were applied to check the expression of angiogenesis-related proteins. Totally, 312 target genes of catalpol and 823 angiogenesis-related targets were obtained with 56 common targets leading to PPI network analysis, highlighting hub genes (AKT1, EGFR, STAT3, MAPK3, and CASP3). These hub genes were mainly enriched in lipid and atherosclerosis pathway and EGFR-related pathway. The in vitro experimental results showed that catalpol achieved a concentration-dependent increase in HUVECs viability. Catalpol also promoted the migration and angiogenesis of HUVECs and up-regulated the expression of EGFR. EGFR knockdown inhibited the effect of catalpol on HUVECs. Catalpol promotes angiogenesis in HUVECs by upregulating EGFR and angiogenesis-related proteins, indicating its potential therapeutic application in vascular-related diseases.
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Cellules endothéliales de la veine ombilicale humaine , Glucosides d'iridoïdes , Pharmacologie des réseaux , Humains , Glucosides d'iridoïdes/pharmacologie , Cellules endothéliales de la veine ombilicale humaine/effets des médicaments et des substances chimiques , Cellules endothéliales de la veine ombilicale humaine/métabolisme , Survie cellulaire/effets des médicaments et des substances chimiques , Cartes d'interactions protéiques/effets des médicaments et des substances chimiques , Récepteurs ErbB/métabolisme , Récepteurs ErbB/génétique , Transduction du signal/effets des médicaments et des substances chimiques , Néovascularisation physiologique/effets des médicaments et des substances chimiques , Mouvement cellulaire/effets des médicaments et des substances chimiques ,RÉSUMÉ
Resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a significant cause of treatment failure and cancer recurrence in non-small cell lung cancer (NSCLC). Approximately 30% of patients with EGFR-activating mutations exhibit primary resistance to EGFR-TKIs. However, the potential mechanisms of primary resistance to EGFR-TKIs remain poorly understood. Recent studies have shown that increased expression of programmed death ligand-1 (PD-L1) is associated with EGFR-TKIs resistance. Therefore, the present study aimed to investigate the mechanism of PD-L1 in primary resistance to EGFR-TKIs in EGFR-mutant lung adenocarcinoma (LUAD) cells. We found that PD-L1 was associated with poor prognosis in patients with EGFR-mutant LUAD, while the combination of EGFR-TKIs with chemotherapy could improve its therapeutic efficacy. In vitro and in vivo experiments revealed that PD-L1 promoted the proliferation and autophagy and inhibited the apoptosis of LUAD cells. Mechanistic studies demonstrated that upregulation of PD-L1 was critical in inducing autophagy through the mitogen-activated protein kinase (MAPK) signaling pathway, which was beneficial for tumor progression and the development of gefitinib resistance. Furthermore, we found that gefitinib combined with pemetrexed could synergistically enhance antitumor efficacy in PD-L1-overexpression LUAD cells. Overall, our study demonstrated that PD-L1 contributed to primary resistance to EGFR-TKIs in EGFR-mutant LUAD cells, which may be mediated by inducing autophagy via the MAPK signaling pathway. These findings not only help improve the prognosis of patients with EGFR-mutant LUAD but also provide a reference for the research of other cancer types.
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Adénocarcinome pulmonaire , Autophagie , Antigène CD274 , Résistance aux médicaments antinéoplasiques , Récepteurs ErbB , Tumeurs du poumon , Système de signalisation des MAP kinases , Mutation , Inhibiteurs de protéines kinases , Humains , Autophagie/effets des médicaments et des substances chimiques , Autophagie/génétique , Récepteurs ErbB/métabolisme , Récepteurs ErbB/génétique , Antigène CD274/métabolisme , Antigène CD274/génétique , Adénocarcinome pulmonaire/génétique , Adénocarcinome pulmonaire/traitement médicamenteux , Adénocarcinome pulmonaire/anatomopathologie , Adénocarcinome pulmonaire/métabolisme , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Résistance aux médicaments antinéoplasiques/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/métabolisme , Animaux , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Mutation/génétique , Souris , Souris nude , Femelle , Mâle , Géfitinib/pharmacologie , Géfitinib/usage thérapeutique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Apoptose/effets des médicaments et des substances chimiques , Souris de lignée BALB CRÉSUMÉ
Epidermal growth factor receptor (EGFR) mutation status is pivotal in predicting the efficacy of tyrosine kinase inhibitor treatments against tumors. Among EGFR mutations, the E746-A750 deletion is particularly common and accurately quantifying it can guide targeted therapies. This study introduces a novel visual sensing technology using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas12a system guided by ligation-initiated loop-mediated isothermal amplification (LAMP) to detect the del E746-A750 mutation in EGFR. Conventional LAMP primers were simplified by designing a pair of target-specific stem-loop DNA probes, enabling selective amplification of the target DNA. The CRISPR/Cas12a system was employed to identify the target nucleic acid and activate Cas12a trans-cleavage activity, thereby enhancing the specificity of the assay. Furthermore, the biosensor utilized high-performance nanomaterials such as triangular gold nanoparticles and graphdiyne, known for their large specific surface area, to enhance sensitivity effectively as a sensing platform. The proposed biosensor demonstrated outstanding specificity, achieving a low detection limit of 17 fM (S/N = 3). Consequently, this innovative strategy not only expands the application scope of CRISPR/Cas12a technology but also introduces a promising approach for clinical diagnostics in modern medicine.
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Techniques de biocapteur , Systèmes CRISPR-Cas , Récepteurs ErbB , Techniques d'amplification d'acides nucléiques , Techniques de biocapteur/méthodes , Systèmes CRISPR-Cas/génétique , Techniques d'amplification d'acides nucléiques/méthodes , Humains , Récepteurs ErbB/génétique , Techniques électrochimiques/méthodes , Limite de détection , Or/composition chimique , Nanoparticules métalliques/composition chimique , Délétion de séquence , Protéines bactériennes , Endodeoxyribonucleases , Techniques de diagnostic moléculaire , Protéines associées aux CRISPRRÉSUMÉ
Fluxes in human copper levels recently garnered attention for roles in cellular signaling, including affecting levels of the signaling molecule cyclic adenosine monophosphate. We herein apply an unbiased temporal evaluation of the signaling and whole genome transcriptional activities modulated by copper level fluctuations to identify potential copper sensor proteins responsible for driving these activities. We find that fluctuations in physiologically relevant copper levels modulate EGFR signal transduction and activation of the transcription factor CREB. Both intracellular and extracellular assays support Cu1+ inhibition of the EGFR phosphatase PTPN2 (and potentially PTPN1)-via ligation to the PTPN2 active site cysteine side chain-as the underlying mechanism. We additionally show i) copper supplementation drives weak transcriptional repression of the copper importer CTR1 and ii) CREB activity is inversely correlated with CTR1 expression. In summary, our study reveals PTPN2 as a physiological copper sensor and defines a regulatory mechanism linking feedback control of copper stimulated EGFR/CREB signaling and CTR1 expression.
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Transporteur-1 du cuivre , Cuivre , Protéine de liaison à l'élément de réponse à l'AMP cyclique , Récepteurs ErbB , Protein Tyrosine Phosphatase, Non-Receptor Type 2 , Transduction du signal , Récepteurs ErbB/métabolisme , Récepteurs ErbB/génétique , Cuivre/métabolisme , Humains , Protéine de liaison à l'élément de réponse à l'AMP cyclique/métabolisme , Transporteur-1 du cuivre/métabolisme , Protein Tyrosine Phosphatase, Non-Receptor Type 2/métabolisme , Protein Tyrosine Phosphatase, Non-Receptor Type 2/génétique , Protein Tyrosine Phosphatase, Non-Receptor Type 1/métabolisme , Protein Tyrosine Phosphatase, Non-Receptor Type 1/génétique , Transcription génétique/effets des médicaments et des substances chimiquesRÉSUMÉ
The standard clinical practice of managing the non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations was elaborated in Chinese expert consensus on nonsmall cell lung cancer with EGFR exon 20 insertion mutations (2023 edition), and this rare subset has gradually attracted attention recently. With the deepening of treatment area exploration and the approval of new targeted drugs, there are more options for the diagnosis and treatment of EGFR ex20ins positive NSCLC patients. Therefore, based on the previous version of consensus, the expert panel has updated this consensus on the standardized clinical diagnosis and treatment of EGFR ex20ins mutation NSCLC through reference to literature and clinical data, and combined with the experts' own clinical experience. The updated recommendations includes disease congnition, testing methods, therapy and recent relevant clinical trials for NSCLC patients with EGFR ex20ins mutation, in order to provide better medication reference for clinical physicians.â©.
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Carcinome pulmonaire non à petites cellules , Consensus , Récepteurs ErbB , Exons , Tumeurs du poumon , Humains , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/diagnostic , Carcinome pulmonaire non à petites cellules/thérapie , Chine , Récepteurs ErbB/génétique , Exons/génétique , Tumeurs du poumon/génétique , Tumeurs du poumon/diagnostic , Tumeurs du poumon/thérapie , Mutagenèse par insertion , MutationRÉSUMÉ
Multiple primary lung cancer (MPLC) refers to patients with two or more primary lesions of lung cancer. It can be divided into synchronous MPLC (sMPLC) and metachronous MPLC (mMPLC) based on the timing of occurrence. In recent years, the detection rate of MPLC has gradually increased. However, considerable controversy exists in distinguishing MPLC from intrapulmonary metastasis (IM), especially when the histopathological types are identical. Given the significant differences in treatment strategies and prognosis in clinical practice currently, accurate diagnosis of MPLC is crucial for personalized precision therapy. Molecular genetics and sequencing technologies offer effective strategies for assessing the clonal origin of tumors. There have been reports of coexisting mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) fusion genes in non-small cell lung cancer, but case of EGFR mutation following an ALK mutation has not been mentioned. This article accurately diagnoses and retrospectively analyzes the clinical data of a case of ALK mutant adenocarcinoma in a male patient who developed an EGFR mutation with multiple metastases four years after surgery, and reviews the relevant literature. This paper aims to deepen the understanding of mMPLC and provide clinical references for the diagnosis and treatment of such patients.â©.
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Kinase du lymphome anaplasique , Carcinome pulmonaire non à petites cellules , Récepteurs ErbB , Tumeurs du poumon , Mutation , Humains , Kinase du lymphome anaplasique/génétique , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/anatomopathologie , Récepteurs ErbB/génétique , Mâle , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Adulte d'âge moyen , Récepteurs à activité tyrosine kinase/génétiqueRÉSUMÉ
Objective: To explore the gene mutation characteristics and the relationship between gene mutations and long-term prognosis in clinical stage â A lung adenocarcinoma patients. Methods: A retrospective analysis was conducted on 63 clinical stage â A lung adenocarcinoma patients who underwent surgical resection at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2007 to October 2012, with documented postoperative recurrence or metastasis, as well as those who had a follow-up duration of 10 years or more without recurrence or metastasis. Whole exome sequencing (WES) technology was used to analyze the gene mutation profiles in tumor tissues and univariate and multivariate Cox regression analysis were used to clarify the influencing factors for patient prognosis. Results: After long term follow-up, 13 out of the 63 patients (21%) experienced recurrence or metastasis. WES technology analysis revealed that the most common tumor related gene mutations occurred in epidermal growth factor receptor (EGFR), with a mutation rate of 65.1% (41/63), followed by tumor protein p53 (TP53), fatatypical cadherin 1 (FAT1), low density lipoprotein receptor-related protein 1B (LRP1B), mechanistic target of rapamycin (MTOR), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG), and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), with mutation rates of 30.2% (19/63), 20.6% (13/63), 15.9% (10/63), 15.9% (10/63), 15.9% (10/63), and 15.9% (10/63), respectively. Multivariate Cox regression analysis showed that PIK3CG mutations (HR=21.52, 95% CI: 3.19-145.01),smoothened (SMO) mutations (HR=35.28, 95% CI: 3.12-398.39), catenin beta 1 (CTNNB1) mutations (HR=332.86, 95% CI: 15.76-7 029.05), colony stimulating factor 1 receptor (CSF1R) mutations (HR=8 109.60, 95% CI: 114.19-575 955.17), and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations (HR=23.65, 95% CI: 1.86-300.43) were independent risk factors affecting the prognosis of clinical stage â A lung adenocarcinoma patients. Conclusions: PIK3CG, SMO, CTNNB1, CSF1R, BRAF gene mutations are closely related to long-term recurrence or metastasis in clinical stage â A lung adenocarcinoma. Patients with these gene mutations should be given closer clinical attention.
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Adénocarcinome pulmonaire , Récepteurs ErbB , Tumeurs du poumon , Mutation , Récidive tumorale locale , Stadification tumorale , Protéine p53 suppresseur de tumeur , Humains , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/chirurgie , Adénocarcinome pulmonaire/génétique , Adénocarcinome pulmonaire/anatomopathologie , Études rétrospectives , Pronostic , Récepteurs ErbB/génétique , Protéine p53 suppresseur de tumeur/génétique , Sérine-thréonine kinases TOR/métabolisme , Sérine-thréonine kinases TOR/génétique , Cadhérines/génétique , Cadhérines/métabolisme , bêta-Caténine/génétique , bêta-Caténine/métabolisme , , Études de suivi , Mâle , Femelle , Adulte d'âge moyen , Protéines de liaison à l'ADN , Récepteurs aux lipoprotéines LDL , Facteurs de transcriptionRÉSUMÉ
Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1-14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48-0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.
Sujet(s)
Carcinome pulmonaire non à petites cellules , Récepteurs ErbB , Géfitinib , Indoles , Tumeurs du poumon , Mutation , Inhibiteurs de protéines kinases , Quinoléines , Humains , Géfitinib/administration et posologie , Géfitinib/effets indésirables , Géfitinib/usage thérapeutique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/anatomopathologie , Quinoléines/administration et posologie , Quinoléines/effets indésirables , Quinoléines/usage thérapeutique , Indoles/administration et posologie , Indoles/usage thérapeutique , Indoles/effets indésirables , Mâle , Femelle , Récepteurs ErbB/génétique , Récepteurs ErbB/antagonistes et inhibiteurs , Adulte d'âge moyen , Sujet âgé , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Inhibiteurs de protéines kinases/effets indésirables , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Adulte , Sujet âgé de 80 ans ou plusRÉSUMÉ
A novel series of substituted thiazolo[5,4-b]pyridine analogues were rationally designed and synthesized via a multi-step synthetic pathway, including Suzuki cross-coupling reaction. The anticancer activity of all forty-five synthesized derivatives was evaluated against HCC827, H1975, and A549 cancer cell lines utilizing the standard MTT assay. A significant number of the thiazolo[5,4-b]pyridine derivatives exhibited potent anticancer activity. Notably, compounds 10b, 10c, 10h, 10i, and 10k emerged as the most promising anticancer agents. The lead compound, N-(3-(6-(2-aminopyrimidin-5-yl)thiazolo[5,4-b]pyridin-2-yl)-2-methylphenyl)-2,5-difluorobenzenesulfonamide (10k), displayed remarkable potency with IC50 values of 0.010 µM, 0.08 µM, and 0.82 µM against the HCC827, NCI-H1975 and A-549 cancer cell lines, respectively, which were comparable to the clinically approved drug Osimertinib. Importantly, the potent derivatives 10b, 10c, 10h, 10i, and 10k exhibited selective cytotoxicity towards cancer cells and showing no toxicity against the normal BEAS-2B cell line at concentrations exceeding 35 µM. Mechanistic studies revealed that the active compound 10k acts as an EGFR-TK autophosphorylation inhibitor in HCC827 cells. Furthermore, apoptosis assays demonstrated that compound 10k induced substantial early apoptosis (31.9 %) and late apoptosis (8.8 %) in cancer cells, in contrast to the control condition exhibiting only 2.0 % early and 1.6 % late apoptosis. Molecular docking simulations of the synthesized compounds revealed that they formed essential hinge interactions and established hydrogen bonding with Cys797, indicating potential target engagement. These findings highlight the potential of the synthesized thiazolo [(Woodburn, 1999; Zigrossi et al., 2022) 5,45,4-b]pyridine derivatives as promising anticancer agents, warranting further investigation for the development of novel targeted therapies against non-small cell lung cancer.
Sujet(s)
Antinéoplasiques , Carcinome pulmonaire non à petites cellules , Prolifération cellulaire , Conception de médicament , Tests de criblage d'agents antitumoraux , Récepteurs ErbB , Tumeurs du poumon , Mutation , Inhibiteurs de protéines kinases , Pyridines , Humains , Récepteurs ErbB/antagonistes et inhibiteurs , Récepteurs ErbB/métabolisme , Récepteurs ErbB/génétique , Antinéoplasiques/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/composition chimique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/anatomopathologie , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/anatomopathologie , Relation structure-activité , Pyridines/pharmacologie , Pyridines/composition chimique , Pyridines/synthèse chimique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Structure moléculaire , Thiazoles/pharmacologie , Thiazoles/composition chimique , Thiazoles/synthèse chimique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Simulation de docking moléculaireRÉSUMÉ
The integration of extrinsic signaling with cell-intrinsic transcription factors can direct progenitor cells to differentiate into distinct cell fates. In the developing Drosophila eye, differentiation of photoreceptors R1-R7 requires EGFR signaling mediated by the transcription factor Pointed, and our single-cell RNA-Seq analysis shows that the same photoreceptors require the eye-specific transcription factor Glass. We find that ectopic expression of Glass and activation of EGFR signaling synergistically induce neuronal gene expression in the wing disc in a Pointed-dependent manner. Targeted DamID reveals that Glass and Pointed share many binding sites in the genome of developing photoreceptors. Comparison with transcriptomic data shows that Pointed and Glass induce photoreceptor differentiation through intermediate transcription factors, including the redundant homologs Scratch and Scrape, as well as directly activating neuronal effector genes. Our data reveal synergistic activation of a multi-layered transcriptional network as the mechanism by which EGFR signaling induces neuronal identity in Glass-expressing cells.
Sujet(s)
Protéines de liaison à l'ADN , Protéines de Drosophila , Drosophila melanogaster , Récepteurs ErbB , Régulation de l'expression des gènes au cours du développement , Neurones , Transduction du signal , Facteurs de transcription , Animaux , Protéines de Drosophila/métabolisme , Protéines de Drosophila/génétique , Facteurs de transcription/métabolisme , Facteurs de transcription/génétique , Récepteurs ErbB/métabolisme , Récepteurs ErbB/génétique , Drosophila melanogaster/génétique , Drosophila melanogaster/métabolisme , Neurones/métabolisme , Neurones/cytologie , Protéines de liaison à l'ADN/métabolisme , Protéines de liaison à l'ADN/génétique , Différenciation cellulaire , Cellules photoréceptrices d'invertébré/métabolisme , Cellules photoréceptrices d'invertébré/cytologie , Protéines de l'oeil/métabolisme , Protéines de l'oeil/génétique , Disques imaginaux/métabolisme , Disques imaginaux/cytologie , Protéines de tissu nerveux , Protéines proto-oncogènes , Récepteur peptidique invertébrésRÉSUMÉ
Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.
Sujet(s)
Carcinome pulmonaire non à petites cellules , Résistance aux médicaments antinéoplasiques , Épigenèse génétique , Récepteurs ErbB , Glycolyse , Tumeurs du poumon , Inhibiteurs de protéines kinases , Transaminases , Humains , Récepteurs ErbB/génétique , Récepteurs ErbB/métabolisme , Résistance aux médicaments antinéoplasiques/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Transaminases/génétique , Transaminases/métabolisme , Inhibiteurs de protéines kinases/pharmacologie , Glycolyse/effets des médicaments et des substances chimiques , Glycolyse/génétique , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/métabolisme , Épigenèse génétique/effets des médicaments et des substances chimiques , Épigenèse génétique/génétique , Souris , Tumeurs du poumon/génétique , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/métabolisme , Tumeurs du poumon/anatomopathologie , Acrylamides/pharmacologie , Animaux , Dérivés de l'aniline/pharmacologie , Lignée cellulaire tumorale , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Protéines tumorales/génétique , Protéines tumorales/métabolisme , Indoles , PyrimidinesRÉSUMÉ
INTRODUCTION: Adaptive mutagenesis observed in colorectal cancer (CRC) cells upon exposure to EGFR inhibitors contributes to the development of resistance and recurrence. Multiple investigations have indicated a parallel between cancer cells and bacteria in terms of exhibiting adaptive mutagenesis. This phenomenon entails a transient and coordinated escalation of error-prone translesion synthesis polymerases (TLS polymerases), resulting in mutagenesis of a magnitude sufficient to drive the selection of resistant phenotypes. METHODS: In this study, we conducted a comprehensive pan-transcriptome analysis of the regulatory framework within CRC cells, with the objective of identifying potential transcriptome modules encompassing certain translesion polymerases and the associated transcription factors (TFs) that govern them. Our sampling strategy involved the collection of transcriptomic data from tumors treated with cetuximab, an EGFR inhibitor, untreated CRC tumors, and colorectal-derived cell lines, resulting in a diverse dataset. Subsequently, we identified co-regulated modules using weighted correlation network analysis with a minKMEtostay threshold set at 0.5 to minimize false-positive module identifications and mapped the modules to STRING annotations. Furthermore, we explored the putative TFs influencing these modules using KBoost, a kernel PCA regression model. RESULTS: Our analysis did not reveal a distinct transcriptional profile specific to cetuximab treatment. Moreover, we elucidated co-expression modules housing genes, for example, POLK, POLI, POLQ, REV1, POLN, and POLM. Specifically, POLK, POLI, and POLQ were assigned to the "blue" module, which also encompassed critical DNA damage response enzymes, for example. BRCA1, BRCA2, MSH6, and MSH2. To delineate the transcriptional control of this module, we investigated associated TFs, highlighting the roles of prominent cancer-associated TFs, such as CENPA, HNF1A, and E2F7. CONCLUSION: We found that translesion polymerases are co-regulated with DNA mismatch repair and cell cycle-associated factors. We did not, however, identified any networks specific to cetuximab treatment indicating that the response to EGFR inhibitors relates to a general stress response mechanism.