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1.
Zhonghua Zhong Liu Za Zhi ; 42(1): 22-29, 2020 Jan 23.
Artículo en Chino | MEDLINE | ID: mdl-32023765

RESUMEN

The successful application of tyrosine kinase inhibitor (TKI) has kicked off the targeted therapy of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) since the discovery of EGFR gene mutations. Patients harboring the two most classic representative mutations of EGFR gene including exon 19 in-frame deletion or exon 21 L858R mutation could get significant clinical benefits from EGFR-TKIs compared to traditional chemotherapy. Among other approximately 10% of EGFR gene mutation type, exon 20 insertion occupies the first place. Available research had demonstrated that EGFR exon 20 insertion in NSCLC was highly malignant and most insertion variants showed de novo drug resistance towards current approved 1(st) to 3(rd) generation EGFR-TKIs, with much poorer clinical prognosis. Currently, there is a lack of comprehensive research and clinical guideline on the treatment of this specific mutation. In this article, we review the pathogenesis, amino acid sequence variants and current management of EGFR exon 20 insertion mutant NSCLC. Moreover, we come up with the emphasis on the treatment challenges and further development of this rigid mutation in NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Mutación , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Exones , Genes erbB-1 , Humanos , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas
2.
Zhonghua Zhong Liu Za Zhi ; 42(1): 74-77, 2020 Jan 23.
Artículo en Chino | MEDLINE | ID: mdl-32023774

RESUMEN

Gene mutations can impair the sensitivity of cancer cells to targeted drugs, and lead to individual differences of clinical therapeutic effects. Epidermal growth factor receptor (EGFR) mutation plays an important role in therapeutic decision-making. Furthermore, some co-existing gene mutations, such as TP53 mutation, can also affect the therapeutic effect and prognosis of patients. Whether EGFR mutation combined with TP53 mutation affects the sensitivity of lung cancer cells to tyrosine kinase inhibitor (TKI) and long-term prognosis of non-small cell lung cancer (NSCLC) patients is still unknown and has attracted more attentions. However, in the current clinical practice, TP53 mutation is not a key factor of therapeutic decision-making, so further studies are needed to clarify the impact of TP53 mutation (including each subtype) on the potential benefits of EGFR-targeted therapy of NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Proteína p53 Supresora de Tumor , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Toma de Decisiones , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Planificación de Atención al Paciente , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genética
3.
Anticancer Res ; 40(2): 1007-1014, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014946

RESUMEN

BACKGROUND/AIM: Myeloid cell leukemia-1 (MCL-1) is a member of the B-cell lymphoma-2 (Bcl-2) family of proteins, which regulate the intrinsic (mitochondrial) apoptotic cascade. MCL-1 inhibits apoptosis, which may be associated with resistance to cancer therapy. Therefore, in this study, the clinical role of MCL-1 in non-small cell lung cancer (NSCLC) was explored. PATIENTS AND METHODS: This retrospective study included 80 patients with stage 1-3A NSCLC, who underwent surgery without preoperative treatment between 2010 and 2011. MCL-1 expression and Ki-67 index were determined via immunohistochemical staining. Apoptotic index (AI) was determined via terminal deoxynucleotidyl transferase dUTP nick end labeling. RESULTS: The receiver operating characteristic curve analysis (area under curve=0.6785) revealed that MCL-1 expression in 30.0% of the NSCLC tumor cells was a significant cut-off for predicting prognosis. Tumors were considered MCL-1-positive if staining was observed in >30% of the cells. Thirty-six tumors (45.0%) were MCL-1-positive. However, there were no significant differences between MCL-1 expression and clinical variables. AI was lower in MCL-1-positive (2.2±3.6%) than in MCL-1-negative (5.2±7.9%) tumors, although the difference was not significant (p=0.1080). The Ki-67 index was significantly higher in MCL-1-positive than in MCL-1-negative tumors (18.0% vs. 3.0%; p<0.001). Five-year survival rate was significantly worse in patients with MCL-1-positive tumors (68.3%) than in those with MCL-1-negative tumors (93.1%, p=0.0057). Univariate [hazard ratio (HR)=5.041, p=0.0013], and multivariate analyses revealed that MCL-1 expression was a significant prognostic factor (HR=3.983, p=0.0411). CONCLUSION: MCL-1 expression in NSCLC cells correlated inversely with AI and positively with Ki-67 index. MCL-1 may serve as a potential prognostic biomarker and a novel therapeutic target in NSCLC.


Asunto(s)
Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Adulto , Anciano , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC
4.
Bratisl Lek Listy ; 121(1): 31-36, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31950837

RESUMEN

OBJECTIVES: One of the best approaches for recognition of protein function is the induction of mutations for a gene knockout. In line with this strategy, gene editing tools allow researchers to induce these mutations. Lung cancer is one of the leading causes of death worldwide. ZEB1 and ZEB2 genes are the candidates for this disease. METHODS: The ZEB1 and ZEB2 knockout in the non-small cell lung cancer cell line (A549 cell) was investigated. Purification of recombination plasmids was performed from bacteria and then was transported to the A549 cell line. The deletion of ZEB1 and ZEB2 were examined by PCR. RESULTS: The results demonstrated the mutation and deletion in ZEB1 and ZEB2 genes. Based on the findings of this study, A549 cells were transfected with the vectors carrying the sgRNA/Cas9, simultaneously. The DNA fragment demonstrated the presence of indels in target sites as well as provided the potential of CRISPR/Cas9 system. CONCLUSION: CRISPR/Cas9 offers a great potential as an efficient technique for editing of ZEB1 and ZEB2 genes in A549 cell line (Tab. 1, Fig. 6, Ref. 44).


Asunto(s)
Sistemas CRISPR-Cas , Carcinoma de Pulmón de Células no Pequeñas , Edición Génica , Neoplasias Pulmonares , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Homeobox 1 de Unión a la E-Box con Dedos de Zinc , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/genética , Edición Génica/métodos , Técnicas de Inactivación de Genes , Humanos , Neoplasias Pulmonares/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética
5.
Anticancer Res ; 40(1): 427-433, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892597

RESUMEN

BACKGROUND/AIM: The role of anti-PD1/PD-L1 therapy (IO) in NSCLC harboring driver mutations is questionable. This study aimed to examine the efficacy of IO in patients with non-small cell lung cancer (NSCLC) with a KRAS mutation (KRAS+). PATIENTS AND METHODS: We retrospectively identified NSCLC patients harboring KRAS mutation treated with IO in our Institution. We analyzed the results in comparison to non-KRAS patients. RESULTS: Among 328 consecutive KRAS+ NSCLC patients, 43 (13.1%) received IO in our Institution. In parallel 117 non-KRAS NSCLC patients treated with IO were selected for comparison. The baseline characteristics were similar between the two groups. No significant difference was observed between KRAS+ and non-KRAS patients in terms of mPFS (4.6 vs. 3.3 months, p=0.58) or OS (8.1 vs. 13.0 months, p=0.38). CONCLUSION: KRAS mutations seem to be irrelevant for selecting patients for IO that could be therefore considered an effective therapy for NSCLC patients, independently of KRAS status.


Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutación/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Anciano , Antígeno B7-H1/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento
6.
Medicine (Baltimore) ; 99(4): e19011, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31977917

RESUMEN

The aim of this study was to investigate the expression of Kif18A in cancerous and paracancerous tissues from 100 patients with nonsmall cell lung cancer (NSCLC).This was a prospective study of 100 patients with pathologically confirmed NSCLC (adenocarcinoma and squamous cell carcinoma [SCC], n = 50/group) that were operated at the Quanzhou First Hospital Affiliated to Fujian Medical University between June 2015 and December 2016. Kif18A protein expression in cancerous and paracancerous normal tissues was detected by western blot and immunohistochemistry.The expression of the Kif18A protein was higher in adenocarcinoma and SCC tissues than in the corresponding paracancerous normal tissues. The expression of the Kif18A protein was higher in highly differentiated tumors, in patients with lymph node metastasis (vs no lymph node metastasis), adenocarcinoma, and in stage III NSCLC. There were no associations between Kif18A expression and age, gender, and pathologic type.The expression of the Kif18A protein by immunohistochemistry was higher in NSCLC tissues than in normal tissues, and was associated with tumor differentiation, lymph node metastasis, and TNM staging. These results could provide a theoretical basis for novel molecular targeted therapies against NSCLC.


Asunto(s)
Adenocarcinoma/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/genética , Cinesina , Neoplasias Pulmonares/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática/genética , Masculino , Persona de Mediana Edad , Estudios Prospectivos
7.
Toxicol Lett ; 320: 37-45, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31778776

RESUMEN

As a major toxicant which is abundant in tobacco smoking, benzo(a)pyrene (BaP) is considered as a strong carcinogen of lung cancer. In spite of the intensive research, the role that BaP plays in lung cancer still lacks a comprehensive and precise understanding. Recently, a long non-coding RNA, linc00673, has emerged as a central player in different kinds of malignancies, including non-small cell lung cancer (NSCLC). In the present study, we found that BaP with the concentration of no more than 8 µM did not affect cell proliferation in the NSCLC cell line A549, while it significantly enhanced A549 cell migration and invasion. Further results revealed that BaP promoted mesenchymal biomarkers expression and inhibited the major epithelial biomarker E-cadherin in a time and dose dependent manner, which indicated epithelial-mesenchymal transition (EMT) was induced by BaP in A549 cells. Through quantitative real-time PCR, we observed that BaP significantly elevated the expression level of linc00673. While after the knockdown of aryl hydrocarbon receptor (AHR), the up-regulating effect of BaP on linc00673 was reversed. Furthermore, silencing linc00673 significantly suppressed the BaP-induced migration, invasion, and EMT in A549 cells. In summary, our study demonstrates that BaP promotes A549 cell migration, invasion and EMT through up-regulating the expression of linc00673 in an AHR-dependent manner.


Asunto(s)
Benzo(a)pireno/toxicidad , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , ARN Largo no Codificante/metabolismo , Células A549 , Antígenos CD/genética , Antígenos CD/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Invasividad Neoplásica , ARN Largo no Codificante/genética , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal , Factores de Tiempo , Regulación hacia Arriba
8.
Life Sci ; 241: 117134, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31811854

RESUMEN

AIMS: Non-small cell lung cancer (NSCLC), characterized by extensive metastasis and poor prognosis, is the most common type of lung cancer. Dysregulation of certain lncRNAs is known to be linked to the tumorigenesis of NSCLC. However, the specific roles in NSCLC for many other lncRNAs, such as linc01088, remain largely unknown. MATERIALS AND METHODS: The expression patterns of linc01088, p21 and EZH2 were examined both in NSCLC tissues and cell lines using RT-qPCR assay. CCK-8, colony formation, immunofluorescence staining, and flow cytometry assays were employed to evaluate the effects of linc01088 on NSCLC cell proliferation properties. RNA immunoprecipitation (RIP) assay was performed to determine the direct binding relationship between linc01088 and zeste homolog 2 (EZH2). Western blot and RT-qPCR analysis were performed to assess p21 level within knockdown of either linc01088 or EZH2. Nude mouse subcutaneous NSCLC models were constructed for further validating the effects and mechanisms of linc01088 in vivo. KEY FINDINGS: linc01088 and EZH2 were highly expressed both in NSCLC tissues and cell lines. Knockdown of linc01088 suppressed the proliferation of NSCLC cells, and prolonged the G1 phase while shortened S and G2-M phases. RIP assay revealed the direct binding relationship between linc01088 and EZH2. Knockdown of either linc01088 or EZH2 induced up-regulation of p21 expression, which subsequently inhibited the tumor growth. SIGNIFICANCE: We demonstrated that linc01088 could promote cell proliferation via binding with EZH2 to repress p21, which aggravates the tumorigenesis of NSCLC. Therefore, linc01088 might be a potential oncogene and target for novel anti-tumor therapies.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/secundario , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , ARN Largo no Codificante/genética , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proliferación Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la Neoplasia , Pronóstico , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
9.
J Cancer Res Clin Oncol ; 146(1): 273-285, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31641854

RESUMEN

PURPOSE: The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway plays a vital role in cancer development and progression. This study aimed to investigate the relationship between genotype variants in mTORC1 pathway and the risk of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC). METHODS: We extracted genomic DNA from blood samples of 501 NSCLC patients and genotyped eight single-nucleotide polymorphisms (SNPs) in three core genes [mammalian target of rapamycin (mTOR), mammalian lethal with sec-13 protein 8 (mLST8) and regulatory-associated protein of mTOR (RPTOR)] of the mTORC1 pathway. The associations between these SNPs and the risk of BM development were assessed. RESULTS: The AG/GG genotype of mLST8:rs26865 and TC/CC genotype of mLST8:rs3160 were associated with an increased risk of BM [hazard ratios (HR) 2.938, 95% confidence interval (CI) 1.664-5.189, p < 0.001 and HR = 2.490, 95% CI = 1.543-4.016, p < 0.001, respectively]. These risk polymorphisms had a cumulative effect on BM risk, with two risk genotypes exhibiting the highest increased risk (p < 0.001). Furthermore, these risk SNPs were associated with the lymph node metastasis (N2/3), body mass index (BMI) (≥ 25 kg/m2), high level of squamous cell carcinoma (SCC) antigen and Ki-67 proliferation index. Moreover, patients with AG/GG genotype of mLST8:rs26865 had significantly lower median overall survival than those with AA genotype (12.1 months versus 21.6 months, p = 0.04). CONCLUSIONS: Our results indicate that polymorphisms in mTORC1 pathway were significantly associated with increased risk of BM and may be valuable biomarkers to identify NSCLC patients with a high risk of BM.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Transducción de Señal
10.
Oncology ; 98(1): 23-28, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31494653

RESUMEN

BACKGROUND: Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), is effective against EGFR-mutated non-small cell lung carcinoma resistant to first- or second-generation EGFR-TKIs in patients in whom an EGFR T790M mutation has been detected. Detection of the T790M mutation using circulating tumor DNA (ctDNA) is less invasive than a tissue re-biopsy, including a transbronchial lung biopsy; however, the prognostic implications of the T790M mutation in ctDNA have not been fully elucidated. METHODS: We retrospectively reviewed the clinical features of non-small cell lung carcinoma patients in whom an EGFR T790M mutation had been detected at our hospital and assessed the clinical outcomes of osimertinib for these patients in terms of detection sites. RESULTS: An EGFR T790M mutation was detected in 32 non-small cell lung carcinoma patients, of whom 21 (65.6%) underwent osimertinib treatment after detection of the mutation. The mutation was detected using plasma samples in 10 patients (47.6%; liquid biopsy group), while it was detected using tissue samples in 11 patients (52.4%; tissue biopsy group). Liver and bone metastases were more frequently observed in patients in the liquid biopsy group than in the tissue biopsy group (30.0 vs. 0% and 60.0 vs. 18.2%, respectively). The median progression-free survival time was significantly shorter in the liquid biopsy group (132.0 days) than in the tissue biopsy group (682.0 days). The median overall survival time in the liquid biopsy group was 376.0 days, whereas that in the tissue biopsy group was not reached during our observation period. CONCLUSIONS: Non-small cell lung carcinoma patients in whom an EGFR T790M mutation was detected in plasma samples demonstrated a poorer response to osimertinib than those in whom the mutation was detected in tissue specimens.


Asunto(s)
Sustitución de Aminoácidos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , ADN Tumoral Circulante , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mutación , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Receptores ErbB/genética , Femenino , Humanos , Biopsia Líquida , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tomografía Computarizada por Rayos X
11.
Life Sci ; 241: 117165, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31838136

RESUMEN

AIMS: Previous work has reported the closely correlation between inflammation and carcinogenesis, while the role of NALP3, the key component of inflammasome activation in NSCLC remains elusive. This study was to unravel the mechanism of NALP3 on modulating NSCLC cancer cell growth. METHODS: IHC and immuno-blot were performed to analyze expression of NALP3 and indicated molecules. CCK-8 and xenograft nude mice assay were used to evaluate cell growth in vitro and in vivo. Bioenergetics assay was performed to measure OXPHOS and aerobic glycolysis. siRNA and shRNA were constructed to knockdown endogenous NALP3 and DNMT1. Co-immunoprecipitation was applied to confirm the interaction between NALP3 and DMAP1. BioProfile FLEX analyzer and Lactate Reagent Kit were used to measure relative level glucose uptake and lactate production. KEY FINDINGS: We reported NALP3 were up-regulated in NSCLC tumor tissues. NALP3 depletion suppressed cancer cell growth in vitro and in vivo. Moreover, data showed depletion of NALP3 promoted cell bioenergetics switch from aerobic glycolysis to OXPHOS. Additionally, we found NALP3 interacted with DMAP1 and alteration of NALP3 increased DNMT1 level. Subsequently, we clarified depletion of DNMT1 significantly suppressed NSCLC cell growth and orchestrated cellular metabolism which was similar to the effects of NALP3 knockdown. Finally, our data showed high NALP3 was associated with poor outcomes, and correlated with TNM stage and differentiation. SIGNIFICANCE: Current study elucidated NALP3 could promote metabolic reprogramming to regulate NSCLC cell growth and suggested that NALP3 may be considered as a novel biomarker and therapeutic target for NSCLC patients.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/secundario , Metabolismo Energético , Regulación Neoplásica de la Expresión Génica , Glucólisis , Neoplasias Pulmonares/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proliferación Celular , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Invasividad Neoplásica , Metástasis de la Neoplasia , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Int J Cancer ; 146(1): 208-222, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31251822

RESUMEN

The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/fisiología , Células Madre Neoplásicas/patología , Oncogenes , Proteínas Tirosina Quinasas/fisiología , Sistemas CRISPR-Cas , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Pronóstico , Proteínas Tirosina Quinasas/genética
13.
J Clin Pathol ; 73(1): 35-41, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31296605

RESUMEN

AIMS: Precision medicine therapy is remodelling the diagnostic landscape of cancer. The success of these new therapies is often based on the presence or absence of a specific mutation in a tumour. The Idylla platform is designed to determine the mutational status of a tumour as quickly and accurately as possible, as a rapid, accurate diagnosis is of the utmost importance for the treatment of patients. This is the first complete prospective study to investigate the robustness of the Idylla platform for EGFR, KRAS and BRAF mutations in non-small cell lung cancer, metastatic colorectal cancer and metastatic melanoma, respectively. METHODS: We compared prospectively the Idylla platform with the results we obtained from parallel high-throughput next-generation sequencing, which is the current gold standard for mutational testing. Furthermore, we evaluated the benefits and disadvantages of the Idylla platform in clinical practice. Additionally, we reviewed all the published Idylla performance articles. RESULTS: There was an overall agreement of 100%, 94% and 94% between the next-generation panel and the Idylla BRAF, KRAS and EGFR mutation test. Two interesting discordant findings among 48 cases were observed and will be discussed together with the advantages and shortcoming of both techniques. CONCLUSION: Our observations demonstrate that the Idylla cartridge for the EGFR, KRAS and BRAF mutations is highly accurate, rapid and has a limited hands-on time compared with next-generation sequencing.


Asunto(s)
Biomarcadores de Tumor/genética , Análisis Mutacional de ADN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Neoplasias/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Melanoma/genética , Melanoma/secundario , Neoplasias/patología , Valor Predictivo de las Pruebas , Estudios Prospectivos , Reproducibilidad de los Resultados , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Flujo de Trabajo
14.
J Oncol Pharm Pract ; 26(1): 206-208, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30760168

RESUMEN

Non-small cell lung adenocarcinoma is the most common type of lung cancer but is often difficult to treat. New treatment options have emerged with the class of tyrosine kinase inhibitors, but it has been found that certain genetic mutations in the epidermal growth factor receptor (EGFR) receptor are not as sensitive to this treatment as others. We present a case of a 78-year-old man who was diagnosed with stage IV non-small cell lung adenocarcinoma with an EGFR exon 20 mutations treated with pemetrexed, nivolumab, and then docetaxel. He has lived over four years after his initial diagnosis. This case illustrates the importance of genetic testing of patients to evaluate for specific gene mutations. It highlights the fact that these patients with exon 20 mutations are not sensitive to tyrosine kinase inhibitor treatment and often respond better to chemotherapeutic agents.


Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Adenocarcinoma del Pulmón/genética , Anciano , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Humanos , Masculino
15.
J Oncol Pharm Pract ; 26(1): 13-22, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30832554

RESUMEN

PURPOSE: To describe the outcomes of a pharmacist-led multi-center, collaborative patient education and proactive adverse event management program in a community-based oncology setting. METHODS: Patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer, newly prescribed with oral afatinib, and monitored as part of the Florida Cancer Specialists patient management program, were included in a retrospective, observational analysis. During follow-up, data were collected on adverse event frequency, and changes in afatinib dosing. Data analyses were descriptive and exploratory in nature. RESULTS: The mean age of the 123 patients included in the analysis was 69 years, and 78% were female. At the time of the analysis, 3 patients had discontinued before receiving treatment, 89 patients had discontinued afatinib treatment, and 31 patients were continuing to receive afatinib treatment. The most common afatinib-related adverse events were diarrhea (85%), rash/skin reactions (58%), stomatitis/mucositis (19%), and paronychia (16%). Overall, 13% of patients discontinued due to afatinib-related adverse events. The median duration of treatment was 4 months in patients who discontinued due to adverse events, 6 months in those who discontinued for other reasons, and 18 months in those who were continuing to receive therapy. Afatinib dose-reductions were more frequent in patients continuing treatment versus those who discontinued due to adverse events (77% vs. 42%, respectively). CONCLUSIONS: Findings suggest that adverse events in patients with EGFRm + non-small cell lung cancer receiving afatinib can be successfully managed in a community-based, real-world setting with the help of collaborative pharmacist-led patient education, adverse event monitoring, and continuous support.


Asunto(s)
Afatinib/efectos adversos , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Educación del Paciente como Asunto/tendencias , Farmacéuticos/tendencias , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Servicios Comunitarios de Farmacia/tendencias , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/terapia , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Educación del Paciente como Asunto/métodos , Relaciones Profesional-Paciente , Estudios Retrospectivos
16.
Int J Cancer ; 146(2): 388-399, 2020 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-31241180

RESUMEN

Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/genética , Fibrosis Pulmonar Idiopática/genética , Neoplasias Pulmonares/genética , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Metilación de ADN , Epigénesis Genética , Femenino , Humanos , Fibrosis Pulmonar Idiopática/complicaciones , Fibrosis Pulmonar Idiopática/patología , Estimación de Kaplan-Meier , Pulmón/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico
17.
Zhonghua Bing Li Xue Za Zhi ; 48(12): 934-939, 2019 Dec 08.
Artículo en Chino | MEDLINE | ID: mdl-31818066

RESUMEN

Objective: To investigate the function and mechanism of hsa_circ_0014130 in lung adenocarcinoma cell line and to find potential molecular inhibitors. Methods: The hsa_circ_0014130 expression level detection and overexpression and subtraction experiments were performed using common cell lines of lung cancer (PC9, H1299, A549, HCC827, and BEAS-2B). qPCR was used to verify the proliferation and invasion of lung cancer cells by MTS and invasion assay, and then the targeted microRNA was searched through the database. Western blot was used to detect the downstream signaling pathways, and finally the effect of small molecule inhibitors was investigated on proliferation and invasion of non-small cell lung cancer. Results: The expression level of hsa_circ_0014130 was up-regulated in the three cell lines, and both the overexpression plasmid and the subtractive siRNA were effectively transfected into the cells. Overexpression of hsa_circ_0014130 was able to promote the proliferation and invasion of tumor cells, and knockdown of hsa_circ_0014130 inhibited the proliferation and invasion of tumor cells. hsa_circ_0014130 was capable to target hsa-miR-566 to reduce its expression level and to inhibit epithelial-to-mesenchymal transition. The use of the small molecule inhibitor SB-431542 and simultaneous reduction of hsa_circ_0014130 significantly inhibited the proliferation and invasion of tumor cells. Conclusions: The hsa_circ_0014130 promotes the invasion and proliferation of lung cancer cells by targeting hsa-miR-566 to enhance the expression of TWIST1, and its expression level can be significantly inhibited by the small molecule inhibitor SB-431542, which significantly inhibits the proliferation and invasion of lung cancer cells. Therefore,hsa_circ_0014130 is a potential lung cancer treatment target.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , /genética , Adenocarcinoma del Pulmón/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , MicroARNs/genética
18.
Pathologe ; 40(Suppl 3): 366-368, 2019 Dec.
Artículo en Alemán | MEDLINE | ID: mdl-31807843

RESUMEN

Although therapy with immune checkpoint inhibitors (ICIs) for patients with non-small-cell lung carcinoma (NSCLC), which has recently become available, does offer a survival advantage compared with chemotherapy, the overall response rate is only around 20 %. Biomarkers are increasingly important in identifying patients who would benefit from ICI therapy. Expression of PD-L1 was the first predictive biomarker to be developed, but was unable to sufficiently predict the efficacy of ICI. Another biomarker, tumour mutation burden (TMB), is defined as the number of mutations per megabase of DNA analysed. Microsatellite instability also acts as a predictive marker for ICI therapy response. Many tumour entities demonstrate a high correlation between MSI and high TMB. Studies show a benefit of progression-free survival for patients with NSCLC and a TMB of at least 10 mutations per megabase.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carga Tumoral/genética , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/genética , Inestabilidad de Microsatélites , Mutación
19.
Eur J Histochem ; 63(4)2019 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-31833327

RESUMEN

Serine-arginine protein kinase (SRPK) belongs to a class of cell cycle regulating kinases that can phosphorylate proteins containing serine/arginine-Rich (SR) regions. SR proteins are a family of RNA binding phosphoproteins that control both constitutive and alternative pre-mRNA splicing events. However, little is known about their role in non-small cell lung cancer (NSCLC). In the present study, we found that serine-arginine protein kinase 2 (SRPK2) expression was upregulated in NSCLC tissues compared with adjacent normal tissues. Kaplan-Meier curve analyses showed that the overall survival time of NSCLC patients with high SRPK2 expression was shorter than those with low SRPK2 expression. Overexpression of SRPK2 promoted NSCLC cell proliferation and cell cycle arrest, while knockdown of SRPK2 inhibited proliferation and promoted cell cycle arrest in NSCLC cell lines. SRPK2 promoted the transcriptional regulation of E2F1 on downstream cell cycle related genes through phosphorylation of SC35. Xenograft model showed that SRPK2 promoted tumor growth in vivo. SRPK2 phosphorylated SC35 and phosphorylated SC35 activated E2F1 transcription of cyclin-related proteins, thereby promoting the cycle progression of NSCLC. Our findings demonstrated that SRPK2 may be a potential therapeutic target for NSCLC clinical therapy, which plays an important role in the progression of NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Puntos de Control del Ciclo Celular/fisiología , Regulación hacia Abajo/fisiología , Factor de Transcripción E2F1/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Anticuerpos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología
20.
J Exp Ther Oncol ; 13(2): 131-138, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31881129

RESUMEN

Background: Continuation maintenance therapy with pemetrexed (PEM) and bevacizumab (BEV) following induction therapy with cisplatin (CDDP), PEM, and BEV is beneficial in advanced non-squamous non-small-cell lung cancer (NS-NSCLC), but the survival benefit of addition of BEV to CDDP/PEM as induction therapy is still unclear. The aim of this phase II study was to evaluate the feasibility and safety of a CDDP/PEM/BEV regimen in Japanese patients with EGFR wild-type NS-NSCLC. Patients and Methods: This study included 25 patients who receive intravenous CDDP, PEM, and BEV (15 mg/kg) from August 2010 to February 2013. The primary endpoint of this study was the response rate (RR) and the secondary endpoint was progression free survival (PFS), overall survival (OS), and safety. Results: The median cycles of induction chemotherapy were four (range 1-6). RR was 64%. Most patients (64%) transitioned to maintenance therapy. The median PFS was 9.7 months. Median OS was 21.6 months. Haematological adverse events reaching grade 3 to 4 were neutropenia (8%) without febrile neutropenia, thrombocytopenia (4%), and anemia (4%). BEV-related non-haematological toxicities of grade 3/4 were hypertension (16%), thrombosis (4%), and gastrointestinal perforation (4%). Each adverse events was controllable, and there were no treatment-related deaths. Conclusions: CDDP/PEM/BEV regimen is effective and tolerable in patients with EGFR wild-type advanced NS-NSCLC, but should be paid attention to some BEV-related toxicities.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Cisplatino/administración & dosificación , Receptores ErbB , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Estadificación de Neoplasias , Pemetrexed/administración & dosificación , Resultado del Tratamiento
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