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1.
Br J Cancer ; 128(12): 2186-2196, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37059804

RESUMEN

BACKGROUND: In EGFR-mutant and MET-amplified lung cancer resistant to EGFR inhibitors, double blockade of EGFR and MET is considered as a reasonable strategy despite increasing toxicity. This study evaluated the single MET inhibition in these specific tumours. METHODS: We investigated the efficacy of a single MET inhibitor in EGFR-mutant, MET-amplified lung cancer cells (HCC827GR) and the matched clinical cases and patient-derived cells. Acquired resistance mechanisms to single MET inhibitor were further explored. RESULTS: Single MET inhibitor sufficiently inhibited the EGFR downstream signalling and proliferation in the HCC827GR cells. The MET-inhibitor-sensitive clones had similar EGFR mutation allele frequency as the MET-inhibitor-resistant clones. The patients with EGFR-mutant, MET-amplified lung cancer resistant to EGFR inhibitors showed definite response to single MET inhibitor but the response duration was not durable. The MET gene copy number in their plasma circulating tumour DNA was significantly decreased during the treatment and was not re-increased after progression. In the cells resistant to single MET inhibitor, the EGFR pathway was reactivated, and gefitinib alone successfully suppressed their growth. CONCLUSIONS: Single MET inhibition produced a short-lived response in EGFR-mutant and MET-amplified lung cancer. A further study of a novel combination therapy schedule is needed to achieve long-lasting efficacy and less toxicity.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Gefitinib , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutación , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-met/genética
2.
Nucleic Acids Res ; 48(11): 6340-6352, 2020 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-32383752

RESUMEN

API5 (APoptosis Inhibitor 5) and nuclear FGF2 (Fibroblast Growth Factor 2) are upregulated in various human cancers and are correlated with poor prognosis. Although their physical interaction has been identified, the function related to the resulting complex is unknown. Here, we determined the crystal structure of the API5-FGF2 complex and identified critical residues driving the protein interaction. These findings provided a structural basis for the nuclear localization of the FGF2 isoform lacking a canonical nuclear localization signal and identified a cryptic nuclear localization sequence in FGF2. The interaction between API5 and FGF2 was important for mRNA nuclear export through both the TREX and eIF4E/LRPPRC mRNA export complexes, thus regulating the export of bulk mRNA and specific mRNAs containing eIF4E sensitivity elements, such as c-MYC and cyclin D1. These data show the newly identified molecular function of API5 and nuclear FGF2, and provide a clue to understanding the dynamic regulation of mRNA export.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/química , Proteínas Reguladoras de la Apoptosis/metabolismo , Factor 2 de Crecimiento de Fibroblastos/química , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Transporte de ARN , ARN Mensajero/metabolismo , Transporte Activo de Núcleo Celular , Núcleo Celular/metabolismo , Cristalografía por Rayos X , Ciclina D1/metabolismo , ARN Helicasas DEAD-box/metabolismo , Factor 4E Eucariótico de Iniciación/metabolismo , Humanos , Modelos Moleculares , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo
3.
Br J Cancer ; 124(1): 290-298, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33204025

RESUMEN

BACKGROUND: Recently, fusion variants of the breast cancer anti-oestrogen-resistance 4 (BCAR4) gene were recurrently discovered in lung adenocarcinoma from the genome-wide studies. However, the functional characterisation of BCAR4 fusion has not been investigated. METHODS: Based on the analysis of RNA-sequencing data, we identified a fusion transcript of CD63-BCAR4 in a Korean patient with lung adenocarcinoma who did not harbour any known activating mutations in EGFR and KRAS genes. To investigate the oncogenic effect of CD63-BCAR4, in vitro and in vivo animal experiments were performed. RESULTS: In vitro experiments showed strongly enhanced cell migration and proliferation by the exogenous expression of CD63-BCAR4 protein in bronchial epithelial cells. Cell migration was notably reduced after knockdown of BCAR4 fusion by small-interfering RNA. The tumorigenic and metastatic capability of the CD63-BCAR4 fusion was confirmed by using the mouse xenograft model. Fusion-overexpressed cells result in metastasis to the liver and lung as well as the primary tumours after subcutaneous injection into mice. Cyclin D1, MMP1, Slug and mesenchymal markers were significantly increased after CD63-BCAR4 overexpression in the in vitro and in vivo experiments. CONCLUSIONS: Taken together, our results suggest a newly identified fusion gene, CD63-BCAR4 as a potential novel oncogene in lung adenocarcinoma.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/genética , Fusión de Oncogenes/genética , ARN Largo no Codificante/genética , Tetraspanina 30/genética , Adenocarcinoma del Pulmón/patología , Animales , Carcinogénesis/genética , Movimiento Celular , Xenoinjertos , Humanos , Neoplasias Pulmonares/patología , Ratones , Proteínas de Fusión Oncogénica/genética
4.
Int J Mol Sci ; 22(22)2021 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-34830169

RESUMEN

(1) Background: Mutations in epidermal growth factor receptor (EGFR) proteins account for many non-small cell lung cancers (NSCLCs), and EGFR tyrosine kinase inhibitors (TKIs) are being used as targeted therapeutics. However, resistance to TKIs continues to increase owing to additional mutations in more than half of the patients receiving EGFR TKI therapy. In addition to targeting new mutations with next-generation therapeutics, it is necessary to find an alternative target to overcome the challenges associated with resistance. (2) Methods: To identify potential alternative targets in patients with NSCLC undergoing targeted therapy, putative targets were identified by transcriptome profiling and validated for their biological and therapeutic effects in vitro and in vivo. (3) Results: ELF3 was found to be differentially expressed in NSCLC, and ELF3 knockdown significantly increased cell death in K-Ras mutant as well as in EGFR L858R/T790M mutation harboring lung cancer cells. We also found that auranofin, an inhibitor of protein kinase C iota (PKCί), a protein upstream of ELF3, effectively induced cell death. (4) Conclusions: Our study suggests that blocking ELF3 is an effective way to induce cell death in NSCLC with K-Ras and EGFR T790M/L858R mutations and thus advocates the use of auranofin as an effective alternative drug to overcome EGFR TKI resistance.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Proteínas de Unión al ADN , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos , Isoenzimas , Neoplasias Pulmonares , Proteína Quinasa C , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-ets , Factores de Transcripción , Células A549 , Sustitución de Aminoácidos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutación Missense , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Proto-Oncogénicas c-ets/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
5.
Bioinformatics ; 34(7): 1086-1091, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29126132

RESUMEN

Motivation: With the discovery of cell-free fetal DNA in maternal blood, the demand for non-invasive prenatal testing (NIPT) has been increasing. To obtain reliable NIPT results, it is important to accurately estimate the fetal fraction. In this study, we propose an accurate and cost-effective method for measuring fetal fractions using single-nucleotide polymorphisms (SNPs). Results: A total of 84 samples were sequenced via semiconductor sequencing using a 0.3× sequencing coverage. SNPs were genotyped to estimate the fetal fraction. Approximately 900 000 SNPs were genotyped, and 250 000 of these SNPs matched the semiconductor sequencing results. We performed SNP imputation (1000Genome phase3 and HRC v1.1 reference panel) to increase the number of SNPs. The correlation coefficients (R2) of the fetal fraction estimated using the ratio of non-maternal alleles when coverage was reduced to 0.01 following SNP imputation were 0.93 (HRC v1.1 reference panel) and 0.90 (1000GP3 reference panel). An R2 of 0.72 was found at 0.01× sequencing coverage with no imputation performed. We developed an accurate method to measure fetal fraction using SNP imputation, showing cost-effectiveness by using different commercially available SNP chips and lowering the coverage. We also showed that semiconductor sequencing, which is an inexpensive option, was useful for measuring fetal fraction. Availability and implementation: python source code and guidelines can be found at https://github.com/KMJ403/fetalfraction-SNPimpute. Contact: kangskim@ajou.ac.kr or sunshinkim3@gmail.com. Supplementary information: Supplementary data are available at Bioinformatics online.


Asunto(s)
Algoritmos , ADN/sangre , Técnicas de Genotipaje/métodos , Polimorfismo de Nucleótido Simple , Diagnóstico Prenatal/métodos , Análisis de Secuencia de ADN/métodos , Alelos , Análisis Costo-Beneficio , Exactitud de los Datos , Femenino , Humanos , Embarazo
6.
BMC Public Health ; 18(1): 528, 2018 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-29678134

RESUMEN

BACKGROUND: Studying human health in areas with industrial contamination is a serious and complex issue. In recent years, attention has increasingly focused on the health implications of large industrial complexes. A variety of potential toxic chemicals have been produced during manufacturing processes and activities in industrial complexes in South Korea. A large number of dyeing industries gathered together in Daegu dyeing industrial complex. The residents near the industrial complex could be often exposed to volatile organic compounds. This study aimed to evaluate VOCs levels in the ambient air of DDIC, to assess the impact on human health risks, and to find more convincing evidences to prove these VOCs emitted from DDIC. METHODS: According to deterministic risk assessment, inhalation was the most important route. Residential indoor, outdoor and personal exposure air VOCs were measured by passive samplers in exposed area and controlled area in different seasons. Satisfaction with ambient environments and self-reported diseases were also obtained by questionnaire survey. The VOCs concentrations in exposed area and controlled area was compared by t-test. The relationships among every VOC were tested by correlation. The values of hazard quotient (HQ) and life cancer risk were estimated. RESULTS: The concentrations of measured VOCs were presented, moreover, the variety of concentrations according the distances from the residential settings to the industrial complex site in exposed area. The residential indoor, outdoor, and personal exposure concentrations of toluene, DMF and chloroform in exposed area were significantly higher than the corresponding concentrations in controlled area both in summer and autumn. Toluene, DMF, chloroform and MEK had significantly positive correlations with each other in indoor and outdoor, and even in personal exposure. The HQ for DMF exceeded 1, and the life cancer risk of chloroform was greater than 10- 4 in exposed area. The prevalence of respiratory diseases, anaphylactic diseases and cardiovascular diseases in exposed area were significantly higher than in controlled area. CONCLUSIONS: This study showed that adverse cancer and non-cancer health effects may occur by VOCs emitted from DDIC, and some risk managements are needed. Moreover, this study provides a convenient preliminarily method for pollutants source characteristics.


Asunto(s)
Contaminantes Atmosféricos/efectos adversos , Colorantes , Exposición a Riesgos Ambientales/efectos adversos , Medición de Riesgo , Industria Textil , Compuestos Orgánicos Volátiles/efectos adversos , Adulto , Anciano , Contaminantes Atmosféricos/análisis , Exposición a Riesgos Ambientales/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , República de Corea/epidemiología , Estaciones del Año , Adulto Joven
7.
Gynecol Oncol ; 145(2): 361-365, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28274569

RESUMEN

OBJECTIVE: To test an electrically conductive chip, incorporating a nanoroughened microfluidic platform for the capture of circulating tumor cells (CTCs), and assess its clinical merit in instances of epithelial ovarian cancer (EOC). METHODS: A total of 54 patients with EOC recruited between August 2014 and May 2015 were enrolled in this prospective study. CTCs in peripheral blood were detected in advance of primary tumor resection and before initiating adjuvant chemotherapy for recurrent disease. We identified CTCs as EpCAM-positive and DAPI-positive, and CD45-negative feature. RESULTS: Twenty-four patients with primary disease and 30 patients with recurrences were included in the study. CTCs were detected in 98.1% (53/54). In newly diagnosed patients, median counts of single CTCs and CTC clusters were 4 (0-13) and 1(0-14), respectively. In those with recurrences, median counts were 3 (1-9) and 1(0-24), respectively. Such counts did not differ significantly by tumor stage or by serum CA125 level; but progression-free survival declined at a cutpoint of ≥3 CTCs, and CTC-cluster positivity correlated with platinum resistance. Isolated CTCs (successfully cultured ex vivo in two patients) showed greater sensitivity to anticancer drugs and proliferated more rapidly than did established cell lines. CONCLUSION: Proof-of-concept was provided for an electrically conductive and nanoroughened microfluidic platform-based chip designed to capture CTCs in patients with EOC. A larger patient sampling and longer duration of follow-up are needed to determine its suitability for clinical use.


Asunto(s)
Neoplasias Glandulares y Epiteliales/sangre , Neoplasias Glandulares y Epiteliales/patología , Células Neoplásicas Circulantes/patología , Neoplasias Ováricas/sangre , Neoplasias Ováricas/patología , Carcinoma Epitelial de Ovario , Línea Celular Tumoral , Femenino , Humanos , Dispositivos Laboratorio en un Chip , Técnicas Analíticas Microfluídicas/instrumentación , Técnicas Analíticas Microfluídicas/métodos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias
8.
Cancer Res ; 84(9): 1491-1503, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38607364

RESUMEN

Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations, particularly in women. EGFR mutations and anaplastic lymphoma kinase (ALK) fusions are major genetic alterations observed in NSLA, and NSLA with these alterations have been well studied and can be treated with targeted therapies. To provide insights into the molecular profile of NSLA without EGFR and ALK alterations (NENA), we selected 141 NSLA tissues and performed proteogenomic characterization, including whole genome sequencing (WGS), transcriptomic, methylation EPIC array, total proteomic, and phosphoproteomic analyses. Forty patients with NSLA harboring EGFR and ALK alterations and seven patients with NENA with microsatellite instability were excluded. Genome analysis revealed that TP53 (25%), KRAS (22%), and SETD2 (11%) mutations and ROS1 fusions (14%) were the most frequent genetic alterations in NENA patients. Proteogenomic impact analysis revealed that STK11 and ERBB2 somatic mutations had broad effects on cancer-associated genes in NENA. DNA copy number alteration analysis identified 22 prognostic proteins that influenced transcriptomic and proteomic changes. Gene set enrichment analysis revealed estrogen signaling as the key pathway activated in NENA. Increased estrogen signaling was associated with proteogenomic alterations, such as copy number deletions in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14. Finally, saracatinib, an Src inhibitor, was identified as a potential drug for targeting activated estrogen signaling in NENA and was experimentally validated in vitro. Collectively, this study enhanced our understanding of NENA NSLA by elucidating the proteogenomic landscape and proposed saracatinib as a potential treatment for this patient population that lacks effective targeted therapies. SIGNIFICANCE: The proteogenomic landscape in never-smoker lung cancer without known driver mutations reveals prognostic proteins and enhanced estrogen signaling that can be targeted as a potential therapeutic strategy to improve patient outcomes.


Asunto(s)
Adenocarcinoma del Pulmón , Quinasa de Linfoma Anaplásico , Receptores ErbB , Estrógenos , Neoplasias Pulmonares , Mutación , Proteogenómica , Transducción de Señal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Variaciones en el Número de Copia de ADN , Receptores ErbB/genética , Receptores ErbB/metabolismo , Estrógenos/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , No Fumadores/estadística & datos numéricos , Pronóstico , Proteogenómica/métodos , Transducción de Señal/genética
9.
Cancers (Basel) ; 16(4)2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38398169

RESUMEN

Intratumor heterogeneity leads to different responses to targeted therapies, even within patients whose tumors harbor identical driver oncogenes. This study examined clinical outcomes according to a patient-derived cell (PDC)-based drug sensitivity test in lung cancer patients treated with targeted therapies. From 487 lung cancers, 397 PDCs were established with a success rate of 82%. In 139 PDCs from advanced non-small-cell lung cancer (NSCLC) patients receiving targeted therapies, the standardized area under the curve (AUC) values for the drugs was significantly correlated with their tumor response (p = 0.002). Among 59 chemo-naive EGFR/ALK-positive NSCLC patients, the PDC non-responders showed a significantly inferior response rate (RR) and progression-free survival (PFS) for the targeted drugs than the PDC responders (RR, 25% vs. 78%, p = 0.011; median PFS, 3.4 months [95% confidence interval (CI), 2.8-4.1] vs. 11.8 months [95% CI, 6.5-17.0], p < 0.001). Of 25 EGFR-positive NSCLC patients re-challenged with EGFR inhibitors, the PDC responder showed a higher RR than the PDC non-responder (42% vs. 15%). Four patients with wild-type EGFR or uncommon EGFR-mutant NSCLC were treated with EGFR inhibitors based on their favorable PDC response to EGFR inhibitors, and two patients showed dramatic responses. Therefore, the PDC-based drug sensitivity test results were significantly associated with clinical outcomes in patients with EGFR- or ALK-positive NSCLC. It may be helpful for predicting individual heterogenous clinical outcomes beyond genomic alterations.

10.
J Immunol ; 187(10): 5211-20, 2011 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-21998452

RESUMEN

We have reported that apoptotic ß cells undergoing secondary necrosis, called "late apoptotic (LA) ß cells," stimulated APCs and induced diabetogenic T cell priming through TLR2, which might be one of the initial events in autoimmune diabetes. Indeed, diabetogenic T cell priming and the development of autoimmune diabetes were significantly inhibited in TLR2-null NOD mice, suggesting the possibility that TLR2 blockade could be used to inhibit autoimmune diabetes. Because prolonged TLR stimulation can induce TLR tolerance, we investigated whether repeated TLR2 administration affects responses to LA ß cells and inhibits autoimmune diabetes in NOD mice by inducing TLR2 tolerance. Treatment of primary peritoneal macrophages with a TLR2 agonist, Pam3CSK(4), suppressed cytokine release in response to LA insulinoma cells or further TLR2 stimulation. The expression of signal transducer IRAK-1 and -4 proteins was decreased by repeated TLR2 stimulation, whereas expression of IRAK-M, an inhibitory signal transducer, was enhanced. Chronic Pam3CSK(4) administration inhibited the development of diabetes in NOD mice. Diabetogenic T cell priming by dendritic cells and upregulation of costimulatory molecules on dendritic cells by in vitro stimulation were attenuated by Pam3CSK(4) administration in vivo. Pam3CSK(4) inhibited diabetes after adoptive transfer of diabetogenic T cells or recurrence of diabetes after islet transplantation by pre-existing sensitized T cells. These results showed that TLR2 tolerance can be achieved by prolonged treatment with TLR2 agonists, which could inhibit priming of naive T cells, as well as the activity of sensitized T cells. TLR2 modulation could be used as a novel therapeutic modality against autoimmune diabetes.


Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/prevención & control , Tolerancia Inmunológica , Receptor Toll-Like 2 , Animales , Apoptosis/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Línea Celular Tumoral , Células Cultivadas , Diabetes Mellitus Tipo 1/patología , Tolerancia Inmunológica/genética , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/patología , Lipopéptidos/administración & dosificación , Lipopéptidos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Transgénicos , Receptor Toll-Like 2/agonistas , Receptor Toll-Like 2/deficiencia , Receptor Toll-Like 2/genética
11.
J UOEH ; 35(2): 137-45, 2013 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-23774657

RESUMEN

Indoor nitrogen dioxide (NO2) concentration is an important factor for personal exposure despite the wide distribution of its sources. Exposure to NO2 may produce adverse health effects. The aims of this study were to characterize the indoor air quality of wayside shops using multiple NO2 measurements, and to estimate the contribution of outdoor NO2 sources such as vehicle emission to indoor air quality. Daily indoor and outdoor NO2 concentrations were measured for 21 consecutive days in wayside shops (5 convenience stores, 5 coffee shops, and 5 restaurants). Contributions of outdoor NO2 sources to indoor air quality were calculated with penetration factors and source strength factors by indoor mass balance model in winter and summer, respectively. Most wayside shops had significant differences in indoor and outdoor NO2 concentrations both in winter and in summer. Indoor NO2 concentrations in restaurants were twice more than those in convenience stores and coffee shops in winter. While outdoor NO2 contributions in indoor convenience stores and coffee shops were dominant, indoor NO2 contributions were dominant in restaurants. These could be explained that indoor NO2 sources such as gas range and smoking mainly affect indoor concentrations comparing to outdoor sources such as vehicle emission. The indoor mass balance model by multiple measurements suggests that quantitative contribution of outdoor air on indoor air quality might be estimated without measurements of ventilation, indoor generation and decay rate.


Asunto(s)
Contaminación del Aire Interior/análisis , Dióxido de Nitrógeno/análisis , Contaminación del Aire/análisis , Emisiones de Vehículos
12.
Biomol Ther (Seoul) ; 31(5): 559-565, 2023 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-36941082

RESUMEN

Ataxia-telangiectasia mutated (ATM), a master kinase of the DNA damage response (DDR), phosphorylates a multitude of substrates to activate signaling pathways after DNA double-strand breaks (DSBs). ATM inhibitors have been evaluated as anticancer drugs to potentiate the cytotoxicity of DNA damage-based cancer therapy. ATM is also involved in autophagy, a conserved cellular process that maintains homeostasis by degrading unnecessary proteins and dysfunctional organelles. In this study, we report that ATM inhibitors (KU-55933 and KU-60019) provoked accumulation of autophagosomes and p62 and restrained autolysosome formation. Under autophagy-inducing conditions, the ATM inhibitors caused excessive autophagosome accumulation and cell death. This new function of ATM in autophagy was also observed in numerous cell lines. Repression of ATM expression using an siRNA inhibited autophagic flux at the autolysosome formation step and induced cell death under autophagy-inducing conditions. Taken together, our results suggest that ATM is involved in autolysosome formation and that the use of ATM inhibitors in cancer therapy may be expanded.

13.
Comput Struct Biotechnol J ; 21: 1978-1988, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36942103

RESUMEN

Alternative splicing (AS) events modulate certain pathways and phenotypic plasticity in cancer. Although previous studies have computationally analyzed splicing events, it is still a challenge to uncover biological functions induced by reliable AS events from tremendous candidates. To provide essential splicing event signatures to assess pathway regulation, we developed a database by collecting two datasets: (i) reported literature and (ii) cancer transcriptome profile. The former includes knowledge-based splicing signatures collected from 63,229 PubMed abstracts using natural language processing, extracted for 202 pathways. The latter is the machine learning-based splicing signatures identified from pan-cancer transcriptome for 16 cancer types and 42 pathways. We established six different learning models to classify pathway activities from splicing profiles as a learning dataset. Top-ranked AS events by learning model feature importance became the signature for each pathway. To validate our learning results, we performed evaluations by (i) performance metrics, (ii) differential AS sets acquired from external datasets, and (iii) our knowledge-based signatures. The area under the receiver operating characteristic values of the learning models did not exhibit any drastic difference. However, random-forest distinctly presented the best performance to compare with the AS sets identified from external datasets and our knowledge-based signatures. Therefore, we used the signatures obtained from the random-forest model. Our database provided the clinical characteristics of the AS signatures, including survival test, molecular subtype, and tumor microenvironment. The regulation by splicing factors was additionally investigated. Our database for developed signatures supported retrieval and visualization system.

14.
Cancers (Basel) ; 15(14)2023 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-37509231

RESUMEN

Although molecular subtypes of small-cell lung cancer (SCLC) have been proposed, their clinical relevance and therapeutic implications are not fully understood. Thus, we aimed to refine molecular subtypes and to uncover therapeutic targets. We classified the subtypes based on gene expression (n = 81) and validated them in our samples (n = 87). Non-SCLC samples were compared with SCLC subtypes to identify the early development stage of SCLC. Single-cell transcriptome analysis was applied to dissect the TME of bulk samples. Finally, to overcome platinum resistance, we performed drug screening of patient-derived cells and cell lines. Four subtypes were identified: the ASCL1+ (SCLC-A) subtype identified as TP53/RB-mutated non-SCLC representing the early development stage of SCLC; the immune activation (SCLC-I) subtype, showing high CD8+/PD-L1+ T-cell infiltration and endothelial-to-mesenchymal transition (EndMT); the NEUROD1 (SCLC-N) subtype, which showed neurotransmission process; and the POU2F3+ (SCLC-P) subtype with epithelial-to-mesenchymal transition (EMT). EndMT was associated with the worst prognosis. While SCLC-A/N exhibited platinum sensitivity, the EndMT signal of SCLC-I conferred platinum resistance. A BET inhibitor suppressed the aggressive angiogenesis phenotype of SCLC-I. We revealed that EndMT development contributed to a poor outcome in SCLC-I. Moreover, heterogenous TME development facilitated platinum resistance. BET inhibitors are novel candidates for overcoming platinum resistance.

15.
J Exp Clin Cancer Res ; 42(1): 37, 2023 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-36717865

RESUMEN

BACKGROUND: A pharmacogenomic platform using patient-derived cells (PDCs) was established to identify the underlying resistance mechanisms and tailored treatment for patients with advanced or refractory lung cancer. METHODS: Drug sensitivity screening and multi-omics datasets were acquired from lung cancer PDCs (n = 102). Integrative analysis was performed to explore drug candidates according to genetic variants, gene expression, and clinical profiles. RESULTS: PDCs had genomic characteristics resembled with those of solid lung cancer tissues. PDC molecular subtyping classified patients into four groups: (1) inflammatory, (2) epithelial-to-mesenchymal transition (EMT)-like, (3) stemness, and (4) epithelial growth factor receptor (EGFR)-dominant. EGFR mutations of the EMT-like subtype were associated with a reduced response to EGFR-tyrosine kinase inhibitor therapy. Moreover, although RB1/TP53 mutations were significantly enriched in small-cell lung cancer (SCLC) PDCs, they were also present in non-SCLC PDCs. In contrast to its effect in the cell lines, alpelisib (a PI3K-AKT inhibitor) significantly inhibited both RB1/TP53 expression and SCLC cell growth in our PDC model. Furthermore, cell cycle inhibitors could effectively target SCLC cells. Finally, the upregulation of transforming growth factor-ß expression and the YAP/TAZ pathway was observed in osimertinib-resistant PDCs, predisposing them to the EMT-like subtype. Our platform selected XAV939 (a WNT-TNKS-ß-catenin inhibitor) for the treatment of osimertinib-resistant PDCs. Using an in vitro model, we further demonstrated that acquisition of osimertinib resistance enhances invasive characteristics and EMT, upregulates the YAP/TAZ-AXL axis, and increases the sensitivity of cancer cells to XAV939. CONCLUSIONS: Our PDC models recapitulated the molecular characteristics of lung cancer, and pharmacogenomics analysis provided plausible therapeutic candidates.


Asunto(s)
Neoplasias Pulmonares , Farmacogenética , Humanos , Fosfatidilinositol 3-Quinasas/genética , Receptores ErbB/metabolismo , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Línea Celular Tumoral , Mutación , Transición Epitelial-Mesenquimal/genética
16.
Bioinformatics ; 27(12): 1731-3, 2011 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-21546394

RESUMEN

SUMMARY: ReMark is a fully automatic tool for clustering orthologs by combining a Recursive and a Markov clustering (MCL) algorithms. The ReMark detects and recursively clusters ortholog pairs through reciprocal BLAST best hits between multiple genomes running software program (RecursiveClustering.java) in the first step. Then, it employs MCL algorithm to compute the clusters (score matrices generated from the previous step) and refines the clusters by adjusting an inflation factor running software program (MarkovClustering.java). This method has two key features. One utilizes, to get more reliable results, the diagonal scores in the matrix of the initial ortholog clusters. Another clusters orthologs flexibly through being controlled naturally by MCL with a selected inflation factor. Users can therefore select the fitting state of orthologous protein clusters by regulating the inflation factor according to their research interests. AVAILABILITY AND IMPLEMENTATION: Source code for the orthologous protein clustering software is freely available for non-commercial use at http://dasan.sejong.ac.kr/~wikim/notice.html, implemented in Java 1.6 and supported on Windows and Linux.


Asunto(s)
Algoritmos , Cadenas de Markov , Proteínas/clasificación , Programas Informáticos , Análisis por Conglomerados , Genoma , Proteínas/genética
17.
Invest New Drugs ; 30(4): 1311-8, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21573958

RESUMEN

Salinomycin (Sal) is potentially useful for the treatment of cancer. The present study examined a novel mechanism of Sal sensitization in cancer cells. Sal sensitized radiation-treated cancer cells by inducing G2 arrest and causing DNA damage. Sal treatment also reduced p21 levels in radiation-treated cells. Considering that Sal sensitizes doxorubicin (DOX)- or etoposide (ETO)-treated cancer cells by causing DNA damage and reducing p21 expression, the results from our study suggest that the mechanism underlying Sal sensitization is conserved in both chemo- and radiation-treated cells. We also tested the ability of Sal to inhibit p-glycoprotein (P-gp), which plays a role in the efflux of anti-cancer drugs to reduce cellular damage. In particular, we compared Sal to verapamil (Ver), a well-known P-gp inhibitor. Sal inhibits P-gp with a different substrate distinct from that of Ver. In addition, Sal sensitized Ver-resistant cells, indicating that this compound is more effective for sensitizing than Ver. Taken together, the results from our study may contribute to the development of Sal-based therapy for cancer patients treated with P-gp-inhibiting drugs or radiation therapy.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Daño del ADN , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Piranos/farmacología , Piranos/uso terapéutico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Línea Celular Tumoral , Terapia Combinada , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias/patología , Especificidad por Sustrato/efectos de los fármacos , Verapamilo/farmacología , Verapamilo/uso terapéutico
18.
Cancers (Basel) ; 14(6)2022 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-35326664

RESUMEN

BACKGROUND: Prediction of resistance mechanisms for epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) remains challenging. Thus, we investigated whether resistant cancer cells that expand shortly after EGFR-TKI treatment would eventually cause the resistant phenotype. METHODS: We generated two EGFR-mutant lung cancer cell lines resistant to gefitinib (PC9GR and HCC827GR). The parent cell lines were exposed to short-term treatment with gefitinib or paclitaxel and then were assessed for EGFR T790M mutation and C-MET expression. These experiments were repeated in vivo and in clinically relevant patient-derived cell (PDC) models. For validation in clinical cases, we measured these gene alterations in plasma circulating tumor DNA (ctDNA) before and 8 weeks after starting EGFR-TKIs in four patients with EGFR-mutant lung cancer. RESULTS: T790M mutation was only detected in the PC9GR cells, whereas C-MET amplification was detected in the HCC827GR cells. The T790M mutation level significantly increased in PC9 cells after short-term treatment with gefitinib but not in the paclitaxel. C-MET mRNA expression was only significantly increased in gefitinib-treated HCC827 cells. We confirmed that the C-MET copy number in HCC827 cells that survived after short-term gefitinib treatment was significantly higher than that in dead HCC827 cells. These findings were reproduced in the in vivo and PDC models. An early on-treatment increase in the plasma ctDNA level of these gene alterations was correlated with the corresponding resistance mechanism to EGFR-TKIs, a finding that was confirmed in post-treatment tumor tissues. CONCLUSIONS: Early on-treatment kinetics in resistance-related gene alterations may predict the final mechanism of EGFR-TKI resistance.

19.
Transl Lung Cancer Res ; 11(9): 1967-1972, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36248327

RESUMEN

Background: Capmatinib, a potent and selective mesenchymalepithelial transition factor (MET) inhibitor, is an effective treatment option for non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations or gene amplification. However, the mechanisms that confer resistance to capmatinib remain elusive. Here, we present a case of primary resistance to capmatinib in a MET-amplified NSCLC patient which was conferred by concurrent MYC amplification. Case Description: Capmatinib was administered as first-line treatment in an 82-year-old MET-amplified [gene copy number (GCN) 13.5] and MET overexpressed (immunohistochemical staining 3+/3, >50%) NSCLC patient. However, the tumor rapidly progressed and showed primary resistance to capmatinib. Next-generation target sequencing using rebiopsy tumor samples revealed MYC amplification. We also performed functional drug susceptibility testing using patient-derived cells (PDCs), which showed overexpression of MYC mRNA and resistance to capmatinib. Meanwhile, ICX-101, an investigational MYC inhibitor, successfully inhibited the growth of PDCs at a relatively low IC50 value. Also, a synergistic effect was shown when capmatinib treatment was followed by ICX-101. Conclusions: Concurrent MYC amplification could potentially confer primary resistance to capmatinib in highly MET amplified NSCLC patients. Further clinical studies are warranted to corroborate these findings, and treatment with MYC inhibitors could be suggested as an alternative therapeutic strategy for this subset of patients.

20.
Front Mol Biosci ; 9: 952651, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36081848

RESUMEN

We previously reported CD63-BCAR4 fusion as a novel oncogene that significantly enhanced cell migration and metastasis in lung cancer. To identify effective inhibitors of metastatic activity induced by BCAR4 fusion, we screened a drug library of 381 FDA-approved compounds. The effect of drugs on cell migration was evaluated by monitoring wound healing. Drugs that decreased the cellular mobility of fusion-overexpressing cells compared with that of control cells were selected as candidates. Library screening revealed that erlotinib, canertinib, and lapatinib demonstrated inhibitory effects on cell migration. Activation of the EGFR signaling pathway was detected after ectopic expression of CD63-BCAR4 in normal bronchial epithelial cells, as observed by the increased phosphorylation of tyrosine residues in the EGFR protein. We also confirmed increased levels of the phosphorylated EGFR protein in resected tumors from mice injected with CD63-BCAR4 overexpressing cells. Tyrosine kinase inhibitors (TKIs) of the EGFR family significantly inhibit the migration of BCAR4 fusion-overexpressing cells and induce apoptosis at high concentrations. Among the EGFR family TKIs, canertinib, a dual EGFR/HER2 inhibitor, showed the best inhibitory effect on the migration and viability of BCAR4 fusion-overexpressing cells. We examined the effect of canertinib in vivo using a mouse xenograft model. Oral administration of canertinib to xenografted mice reduced tumor growth induced by the CD63-BCAR4 fusion gene. In addition, canertinib treatment restored E-cadherin expression and reduced the expression of epithelial-mesenchymal transition regulatory factors such as Slug and Snail. Taken together, these results suggest that EGFR/HER2 inhibitors are potential therapeutic options for BCAR4 fusion-harboring lung cancer patients, even in the absence of EGFR mutations.

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