ABSTRACT
There are no standard third-line or beyond treatments for patients with driver mutation-positive advanced lung adenocarcinoma (LUAD). Anlotinib was approved as a third-line multitarget drug in China in 2018. Limited data are available regarding the efficacy and safety of anlotinib compared with chemotherapy. To investigate the efficacy and safety of anlotinib compared with traditional chemotherapy in patients with epidermal growth factor receptor (EGFR)-positive advanced LUAD. We conducted a retrospective study of 83 EGFR mutation-positive patients with advanced LUAD between 2011 and 2022. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints, whereas the objective response rate (ORR) and disease control rate (DCR) were the secondary endpoints. Anlotinib-related adverse events (AEs) were recorded to evaluate the safety of anlotinib. 39 patients with LUAD received anlotinib and 44 patients with LUAD received chemotherapy were enrolled in the study. Patients treated with anlotinib exhibited longer PFS (11.2 vs 4.5 months, P < .01) and OS (18.8 vs 15.8 months, P < .05) than patients treated with chemotherapy. There were no significant differences in ORR (7.9% vs 20.5%, P = .129) or DCR (100% vs 93.2%, P = .120) between the two groups. Anlotinib-related AEs grading 3-4 level were observed in 2 (5.1%) patients, no anlotinib-related death was recorded. Cox regression analyses of PFS and OS showed that brain metastases and age < 30 years at diagnosis had negative effects on clinical outcomes. Anlotinib is effective and safe in patients with EGFR-positive advanced LUAD. Patients without brain metastases had better clinical outcomes.
Subject(s)
Adenocarcinoma of Lung , ErbB Receptors , Indoles , Lung Neoplasms , Quinolines , Humans , Male , Female , Indoles/therapeutic use , Indoles/adverse effects , Indoles/administration & dosage , Quinolines/adverse effects , Quinolines/therapeutic use , Quinolines/administration & dosage , Middle Aged , ErbB Receptors/genetics , ErbB Receptors/metabolism , Aged , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/mortality , Retrospective Studies , Adult , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Treatment Outcome , Mutation , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Neoplasm Staging , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effectsABSTRACT
Various factors can affect the survival of patients with oropharyngeal cancer. We assessed the expression of protein p16INK4a, Flotillin2, epidermal growth factor receptor, and other clinicopathological features and their prognostic value for this type of cancer. We gathered patient data on demographics, clinicopathological characteristics, treatment patterns, and outcomes. Histologically and by immunochemistry staining we determined expression of prognostic factors and molecular biomarkers. The primary endpoints were overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). Survival was assessed using the Kaplan-Meier method and Cox regression model analyses of potential prognostic parameters. After a median follow-up of 78 months, the median OS was 41 months, with an event recorded in 77.8% of patients. Median DFS was 22 months, 37 patients (51.4%) had disease relapse. The DSS survival rate was 58.3% with a median survival of 68 months. In regards to molecular biomarkers previously mentioned, there was no statistical significance for survival categories. After conducting a multivariate analysis of significant variables, we found that only recurrence, vascular invasion, and surgical intervention remained as factors with independent effects on both OS and DFS. Recurrence and the N stage were identified as independent prognostic factors for DSS. Our analysis underscores the complexity of factors that collectively influence survival following the diagnosis of OPSCC. Several factors were found to be statistically significant. These factors included the type of surgical procedure, disease relapse, vascular invasion, lymphatic invasion, perineural invasion, advanced T stage of the disease, N stage of the disease, and smoking status. The significance of these factors may vary across different types of survival. This analysis did not find any significant impact on survival from the growth factors tested, namely epidermal growth factor receptor, Flotillin2, and p16INK4a, in the applied regression models.
Subject(s)
Biomarkers, Tumor , Cyclin-Dependent Kinase Inhibitor p16 , ErbB Receptors , Membrane Proteins , Oropharyngeal Neoplasms , Humans , Male , Female , Oropharyngeal Neoplasms/mortality , Oropharyngeal Neoplasms/pathology , Oropharyngeal Neoplasms/metabolism , ErbB Receptors/metabolism , Middle Aged , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Membrane Proteins/metabolism , Prognosis , Aged , Biomarkers, Tumor/metabolism , Adult , Disease-Free Survival , Kaplan-Meier Estimate , Aged, 80 and over , Retrospective StudiesABSTRACT
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.
Subject(s)
DNA-Binding Proteins , Drosophila Proteins , Drosophila melanogaster , ErbB Receptors , Gene Expression Regulation, Developmental , Neurons , Signal Transduction , Transcription Factors , Animals , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , ErbB Receptors/metabolism , ErbB Receptors/genetics , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Neurons/metabolism , Neurons/cytology , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Cell Differentiation , Photoreceptor Cells, Invertebrate/metabolism , Photoreceptor Cells, Invertebrate/cytology , Eye Proteins/metabolism , Eye Proteins/genetics , Imaginal Discs/metabolism , Imaginal Discs/cytology , Nerve Tissue Proteins , Proto-Oncogene Proteins , Receptors, Invertebrate PeptideABSTRACT
Aim: The main goal was to create two new groups of indole derivatives, hydrazine-1-carbothioamide (4a and 4b) and oxadiazole (5, and 6a-e) that target EGFR (4a, 4b, 5) or VEGFR-2 (6a-e). Materials & methods: The new derivatives were characterized using various spectroscopic techniques. Docking studies were used to investigate the binding patterns to EGFR/VEGFR-2, and the anti-proliferative properties were tested in vitro. Results: Compounds 4a (targeting EGFR) and 6c (targeting VEGFR-2) were the most effective cytotoxic agents, arresting cancer cells in the G2/M phase and inducing the extrinsic apoptosis pathway. Conclusion: The results of this study show that compounds 4a and 6c are promising cytotoxic compounds that inhibit the tyrosine kinase activity of EGFR and VEGFR-2, respectively.
[Box: see text].
Subject(s)
Antineoplastic Agents , Cell Proliferation , ErbB Receptors , Indoles , Vascular Endothelial Growth Factor Receptor-2 , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Indoles/chemistry , Indoles/pharmacology , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , /pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
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.
Subject(s)
ErbB Receptors , Gene Expression Profiling , Lung Neoplasms , Mutation , Tumor Microenvironment , Humans , ErbB Receptors/genetics , ErbB Receptors/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Tumor Microenvironment/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Gene Expression Regulation, Neoplastic , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/immunology , Adenocarcinoma of Lung/pathology , Transcriptome , Single-Cell AnalysisABSTRACT
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.
Subject(s)
Human Umbilical Vein Endothelial Cells , Iridoid Glucosides , Network Pharmacology , Humans , Iridoid Glucosides/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Cell Survival/drug effects , Protein Interaction Maps/drug effects , ErbB Receptors/metabolism , ErbB Receptors/genetics , Signal Transduction/drug effects , Neovascularization, Physiologic/drug effects , Cell Movement/drug effects , AngiogenesisABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Drug Resistance, Neoplasm , Epigenesis, Genetic , ErbB Receptors , Glycolysis , Lung Neoplasms , Protein Kinase Inhibitors , Transaminases , Humans , ErbB Receptors/genetics , ErbB Receptors/metabolism , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/drug effects , Transaminases/genetics , Transaminases/metabolism , Protein Kinase Inhibitors/pharmacology , Glycolysis/drug effects , Glycolysis/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/metabolism , Epigenesis, Genetic/drug effects , Epigenesis, Genetic/genetics , Mice , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Acrylamides/pharmacology , Animals , Aniline Compounds/pharmacology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Indoles , PyrimidinesABSTRACT
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.
Subject(s)
Adenocarcinoma of Lung , Autophagy , B7-H1 Antigen , Drug Resistance, Neoplasm , ErbB Receptors , Lung Neoplasms , MAP Kinase Signaling System , Mutation , Protein Kinase Inhibitors , Humans , Autophagy/drug effects , Autophagy/genetics , ErbB Receptors/metabolism , ErbB Receptors/genetics , B7-H1 Antigen/metabolism , B7-H1 Antigen/genetics , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/drug effects , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Animals , MAP Kinase Signaling System/drug effects , Cell Line, Tumor , Mutation/genetics , Mice , Mice, Nude , Female , Male , Gefitinib/pharmacology , Gefitinib/therapeutic use , Cell Proliferation/drug effects , Apoptosis/drug effects , Mice, Inbred BALB CABSTRACT
Targeting wild-type epidermal growth factor receptor (EGFR) using tyrosine kinase inhibitors (TKIs) never achieved its purported success in cancers such as head and neck squamous cell carcinoma, which are largely EGFR-dependent. We had previously shown that exceptional responders to TKIs have a genetic aberration that results in overexpression of an EGFR splice variant, isoform D (IsoD). IsoD lacks an integral transmembrane and kinase domain and is secreted in extracellular vesicles (EVs) in TKI-sensitive patient-derived cultures. Remarkably, the exquisite sensitivity to TKIs could be transferred to TKI-resistant tumor cells, and IsoD protein in the EV is necessary and sufficient to transfer the phenotype in vitro and in vivo across multiple models and drugs. This drug response requires an intact endocytic mechanism, binding to full-length EGFR, and signaling through Src-phosphorylation within the endosomal compartment. We propose a therapeutic strategy using EVs containing EGFR IsoD as a co-drug to expand the use of TKI therapy to EGFR-driven cancers.
Subject(s)
Carcinoma, Squamous Cell , ErbB Receptors , Extracellular Vesicles , Protein Isoforms , Protein Kinase Inhibitors , ErbB Receptors/metabolism , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Humans , Protein Kinase Inhibitors/pharmacology , Extracellular Vesicles/metabolism , Protein Isoforms/metabolism , Protein Isoforms/genetics , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Animals , Cell Line, Tumor , Mice , Signal Transduction/drug effects , Phosphorylation/drug effects , Drug Resistance, Neoplasm/drug effects , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/genetics , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/geneticsABSTRACT
The ability of Staphylococcus aureus (S. aureus) to survive within macrophages is a critical strategy for immune evasion, contributing to the pathogenesis and progression of osteomyelitis. However, the underlying mechanisms remain poorly characterized. This study discovered that inhibiting the MEK1/2 pathway reduced bacterial load and mitigated bone destruction in a mouse model of S. aureus osteomyelitis. Histological staining revealed increased phosphorylated MEK1/2 levels in bone marrow macrophages surrounding abscess in the mouse model of S. aureus osteomyelitis. Activation of MEK1/2 pathway and its roles in impairing macrophage bactericidal function were confirmed in primary mouse bone marrow-derived macrophages (BMDMs). Transcriptome analysis and in vitro experiments demonstrated that S. aureus activates the MEK1/2 pathway through EGFR signaling. Moreover, we found that excessive activation of EGFR-MEK1/2 cascade downregulates mitochondrial reactive oxygen species (mtROS) levels by suppressing Chek2 expression, thereby impairing macrophage bactericidal function. Furthermore, pharmacological inhibition of EGFR signaling prevented upregulation of phosphorylated MEK1/2 and restored Chek2 expression in macrophages, significantly enhancing S. aureus clearance and improving bone microstructure in vivo. These findings highlight the critical role of the EGFR-MEK1/2 cascade in host immune defense against S. aureus, suggesting that S. aureus may reduce mtROS levels by overactivating the EGFR-MEK1/2 cascade, thereby suppressing macrophage bactericidal function. Therefore, combining EGFR-MEK1/2 pathway blockade with antibiotics could represent an effective therapeutic approach for the treatment of S. aureus osteomyelitis.
Subject(s)
ErbB Receptors , MAP Kinase Kinase 1 , Macrophages , Osteomyelitis , Staphylococcal Infections , Staphylococcus aureus , Animals , Osteomyelitis/microbiology , Osteomyelitis/immunology , Osteomyelitis/metabolism , Staphylococcal Infections/immunology , Staphylococcal Infections/metabolism , Staphylococcal Infections/microbiology , Mice , Staphylococcus aureus/immunology , ErbB Receptors/metabolism , Macrophages/immunology , Macrophages/metabolism , Macrophages/microbiology , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/metabolism , MAP Kinase Signaling System/physiology , Mice, Inbred C57BL , Disease Models, Animal , Signal TransductionABSTRACT
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.
Subject(s)
Copper Transporter 1 , Copper , Cyclic AMP Response Element-Binding Protein , ErbB Receptors , Protein Tyrosine Phosphatase, Non-Receptor Type 2 , Signal Transduction , ErbB Receptors/metabolism , ErbB Receptors/genetics , Copper/metabolism , Humans , Cyclic AMP Response Element-Binding Protein/metabolism , Copper Transporter 1/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics , Transcription, Genetic/drug effectsABSTRACT
It is well known how the precise localization of glioblastoma multiforme (GBM) predicts the direction of tumor spread in the surrounding neuronal structures. The aim of the present review is to reveal the lateralization of GBM by evaluating the anatomical regions where it is frequently located as well as the main molecular alterations observed in different brain regions. According to the literature, the precise or most frequent lateralization of GBM has yet to be determined. However, it can be said that GBM is more frequently observed in the frontal lobe. Tractus and fascicles involved in GBM appear to be focused on the corticospinal tract, superior longitudinal I, II and III fascicles, arcuate fascicle long segment, frontal strait tract, and inferior frontooccipital fasciculus. Considering the anatomical features of GBM and its brain involvement, it is logical that the main brain regions involved are the frontaltemporalparietaloccipital lobes, respectively. Although tumor volumes are higher in the right hemisphere, it has been determined that the prognosis of patients diagnosed with cancer in the left hemisphere is worse, probably reflecting the anatomical distribution of some detrimental alterations such as TP53 mutations, PTEN loss, EGFR amplification, and MGMT promoter methylation. There are theories stating that the right hemisphere is less exposed to external influences in its development as it is responsible for the functions necessary for survival while tumors in the left hemisphere may be more aggressive. To shed light on specific anatomical and molecular features of GBM in different brain regions, the present review article is aimed at describing the main lateralization pathways as well as gene mutations or epigenetic modifications associated with the development of brain tumors.
Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Glioblastoma/genetics , Glioblastoma/pathology , Glioblastoma/metabolism , ErbB Receptors/genetics , ErbB Receptors/metabolism , Mutation , Glioma/genetics , Glioma/pathology , Glioma/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Prognosis , DNA Repair Enzymes/genetics , DNA Repair Enzymes/metabolism , DNA Modification Methylases/genetics , DNA Modification Methylases/metabolismABSTRACT
The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Herein, we describe the discovery of DS06652923, a novel, potent, and orally available EGFR-triple-mutant inhibitor. Through scaffold hopping from the previously reported nicotinamide derivative, a novel biaryl scaffold was obtained. The potency was successfully enhanced by the introduction of basic substituents based on analysis of the docking study results. In addition, the difluoromethoxy group on the pyrazole ring improved the kinase selectivity by inducing steric clash with the other kinases. The most optimized compound, DS06652923, achieved tumor regression in the Ba/F3 allograft model upon its oral administration.
Subject(s)
Antineoplastic Agents , ErbB Receptors , Mutation , Protein Kinase Inhibitors , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , ErbB Receptors/genetics , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Humans , Administration, Oral , Animals , Structure-Activity Relationship , Mice , Drug Discovery , Molecular Docking Simulation , Molecular Structure , Cell Line, Tumor , Drug Screening Assays, Antitumor , Cell Proliferation/drug effectsABSTRACT
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.
Subject(s)
Apoptosis , ErbB Receptors , Lung Neoplasms , Mutation , Single-Cell Analysis , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/drug therapy , ErbB Receptors/metabolism , ErbB Receptors/genetics , Humans , Apoptosis/genetics , Apoptosis/drug effects , Animals , Mice , Mutation/genetics , Gene Expression Regulation, Neoplastic , Cell Line, Tumor , RNA-Seq , Transcriptome/genetics , Drug Resistance, Neoplasm/genetics , Protein Kinase Inhibitors/pharmacology , Mice, Transgenic , Gene Expression Profiling , bcl-X Protein/metabolism , bcl-X Protein/genetics , Single-Cell Gene Expression AnalysisABSTRACT
Epithelial-mesenchymal transition (EMT) is a cellular process in embryonic development, wound healing, organ fibrosis, and cancer metastasis. Previously, we and others have reported that proinflammatory cytokine interleukin-1ß (IL-1ß) induces EMT. However, the exact mechanisms, especially the signal transduction pathways, underlying IL-1ß-mediated EMT are not yet completely understood. Here, we found that IL-1ß stimulation leads to the partial EMT-like phenotype in human lung epithelial A549 cells, including the gain of mesenchymal marker (vimentin) and high migratory potential, without the complete loss of epithelial marker (E-cadherin). IL-1ß-mediated partial EMT induction was repressed by PI3K inhibitor LY294002, indicating that the PI3K/AKT pathway plays a significant role in the induction. In addition, ERK1/2 inhibitor FR180204 markedly inhibited the IL-1ß-mediated partial EMT induction, demonstrating that the MEK/ERK pathway was also involved in the induction. Furthermore, we found that the activation of the PI3K/AKT and MEK/ERK pathways occurred downstream of the epidermal growth factor receptor (EGFR) pathway and the IL-1 receptor (IL-1R) pathway, respectively. Our findings suggest that the PI3K/AKT and MEK/ERK pathways coordinately promote the IL-1ß-mediated partial EMT induction. The inhibition of not one but both pathways is expected yield clinical benefits by preventing partial EMT-related disorders such as organ fibrosis and cancer metastasis.
Subject(s)
Epithelial-Mesenchymal Transition , Interleukin-1beta , MAP Kinase Signaling System , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Humans , Interleukin-1beta/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , A549 Cells , ErbB Receptors/metabolismABSTRACT
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.
Subject(s)
Cetuximab , Colorectal Neoplasms , Gene Expression Regulation, Neoplastic , Cetuximab/pharmacology , Cetuximab/therapeutic use , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic/drug effects , Cell Line, Tumor , DNA-Directed DNA Polymerase/metabolism , DNA-Directed DNA Polymerase/genetics , Gene Regulatory Networks , Gene Expression Profiling , ErbB Receptors/metabolism , ErbB Receptors/genetics , Mad2 Proteins/genetics , Mad2 Proteins/metabolism , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Agents, Immunological/therapeutic useABSTRACT
TORC1 (target of rapamycin complex 1) is a highly conserved protein kinase that plays a central role in regulating cell growth. Given the role of mammalian TORC1 (mTORC1) in metabolism and disease, understanding mTORC1 downstream signaling and feedback loops is important. mTORC1 recognizes some of its substrates via a five amino acid binding sequence called the TOR signaling (TOS) motif. mTORC1 binding to a TOS motif facilitates phosphorylation of a distinct, distal site. Here, we show that LST2, also known as ZFYVE28, contains a TOS motif (amino acids 401 to 405) and is directly phosphorylated by mTORC1 at serine 670 (S670). mTORC1-mediated S670 phosphorylation promotes LST2 monoubiquitination on lysine 87 (K87). Monoubiquitinated LST2 is stable and displays a broad reticular distribution. When mTORC1 is inactive, unphosphorylated LST2 is degraded by the proteasome. The absence of LST2 enhances EGFR (epidermal growth factor receptor) signaling. We propose that mTORC1 negatively feeds back on its upstream receptor EGFR via LST2.
Subject(s)
ErbB Receptors , Mechanistic Target of Rapamycin Complex 1 , Signal Transduction , Ubiquitination , Mechanistic Target of Rapamycin Complex 1/metabolism , Phosphorylation , Humans , ErbB Receptors/metabolism , HEK293 Cells , Animals , Amino Acid MotifsABSTRACT
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.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , ErbB Receptors , Lung Neoplasms , Mutation , Protein Kinase Inhibitors , Pyridines , Humans , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , ErbB Receptors/genetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Structure-Activity Relationship , Pyridines/pharmacology , Pyridines/chemistry , Pyridines/chemical synthesis , Cell Proliferation/drug effects , Cell Line, Tumor , Molecular Structure , Thiazoles/pharmacology , Thiazoles/chemistry , Thiazoles/chemical synthesis , Drug Resistance, Neoplasm/drug effects , Dose-Response Relationship, Drug , Molecular Docking SimulationABSTRACT
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) plays an important role in the progression of multiple solid tumors and induces resistance to epidermal growth factor receptor (EGFR) target treatment. However, the expression status and the clinical significance of HER2 in oral squamous cell carcinoma (OSCC) is still controversial. Pyrotinib (PYR) is a promising novel EGFR/HER2 dual inhibitor, whose efficacy in OSCC has not been determined. METHODS: 57 locally advanced de novo OSCC patients were included in this study to investigate the relationship between the HER2 expression levels and the prognosis by the tissue microarray analysis (TMA). In vitro and in vivo experiments were performed to retrieve the efficacy of PYR in OSCC. The main downstream of HER2 was evaluated by western blotting in OSCC cell lines and xenograft tumors to explore the potential mechanism of PYR. RESULTS: This study revealed the primary tumor of OSCC had higher HER2 expression levels. Patients with HER2 overexpression had poor overall survival (P < 0.014) and poor disease free survival (P < 0.042). In vitro, PYR suppressed the proliferation, colony formation and migration of OSCC cells. It also promoted apoptosis of OSCC cells and induced cell cycle arrest. Furthermore, PYR was able to inhibit the occurrence and development of OSCC effectively in vivo. Western blotting revealed that PYR suppressed OSCC by inhibiting the phosphorylation of HER2, AKT and ERK. CONCLUSIONS: This study exhibited the anti-OSCC effects of PYR in vitro and in vivo, and demonstrated PYR inhibited OSCC cells by inducing apoptosis via the HER2/ AKT and ERK pathway. The result of this study also indicated locally advanced OSCC patients might benefit from HER2 assay and EGFR/HER2 dual inhibit treatment.