RESUMEN
Comprehensive genomic profiling is highly recommended for treatment decision in nonsquamous, non-small cell lung cancer (NSCLC). However, rare genomic alterations are still being unveiled, with scarce data to guide therapy. Herein, we describe the treatment journey of a 56-year-old, never-smoker Caucasian woman with a metastatic NSCLC harboring a CD47-MET fusion, initially classified as a variant of unknown significance. She had undergone 3 lines of therapy over the course of 3 years, including chemotherapy, immunotherapy, and anti-angiogenic therapy. After reanalysis of her next-generation sequencing data in our service, the fusion was reclassified as likely oncogenic. The patient was started with fourth-line capmatinib, with a good tolerance so far and a complete metabolic response in the active sites of disease, currently ongoing for 18 months. In conclusion, we highlight the sensitivity of a novel MET fusion to capmatinib and emphasize the need for comprehensive panels in NSCLC and molecular tumor board discussions with specialized centers when rare findings arise.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-met , Humanos , Femenino , Persona de Mediana Edad , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas c-met/genética , Acrilamidas/uso terapéutico , Benzamidas/uso terapéutico , Proteínas de Fusión Oncogénica/genética , Triazinas/uso terapéutico , ImidazolesRESUMEN
BACKGROUND: Mesenchymal epithelial transition factor (MET) is a rare oncologic driver gene, and information on immunotherapy for non-small cell lung cancer (NSCLC) patients with this driver gene is limited. Here we evaluate the efficacy and safety of immune checkpoint inhibitors (ICI) under different therapeutic regimen for NSCLC patients with MET alterations. METHODS: From June 2019 to December 2023, we assessed the efficacy and toxicity of ICIs in 42 NSCLC patients with MET alterations. Survival curves were plotted using the Kaplan-Meier method and the Cox proportional hazards model applied for univariate and multivariate analyses. We assessed the size of target lesion according to RECIST v1.1, and objective response rate (ORR) was defined as the sum of complete response (CR) and partial response (PR), disease control rate (DCR) as the sum of CR, PR, and disease stable. RESULTS: A total of 42 NSCLC patients with MET alterations were included in this retrospective study, 10 was MET 14 skipping mutation and 32 was MET amplification. The ORR for ICI treatment was 30.95% and the DCR was 71.43%. Median progression-free survival (mPFS) and median overall survival (OS) were 4.40 and 13.97 months, respectively. There exists statistical differences between the mPFS of ICI monotherapy and combine ICI therapy (2.8 vs 7.8 months, p = 0.022). The incidence of drug-related adverse reactions was 47.62%, mainly bone marrow suppression (14.28%), immune-related pneumonia (7.14%), and liver function impairment (7.14%), and six patients (14.28%) experiencing grade 3 or above adverse events. CONCLUSION: NSCLC patients with MET alterations can benefit from immunotherapy, especially the patients treated by combined ICI therapy. However, special attention should be paid to the occurrence of grade 3/4 adverse reactions while using the combined ICI therapy.
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Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas c-met , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Femenino , Proteínas Proto-Oncogénicas c-met/genética , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Adulto , Supervivencia sin Progresión , Inmunoterapia/efectos adversos , Anciano de 80 o más Años , Estimación de Kaplan-Meier , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: About 50-60% treatment-naïve advanced non-small-cell lung cancers were coexistence of epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition (MET) overexpression. However, few studies demonstrated the prognostic value of MET protein expression in untreated EGFR-mutant lung adenocarcinoma (LUAD). METHODS: A total of 235 EGFR-mutant untreated advanced LUAD patients were retrospectively enrolled. MET expression was determined using immunohistochemistry, and MET positivity was defined as 2 + or 3 + using the METmab scoring algorithm. Progression-free survival (PFS) and overall survival (OS) were analysed according to MET expression status. Independent factors predicting prognosis were identified using multivariate Cox regression analyses. RESULTS: Of the 235 patients, 113 (48.1%) harboured exon 19 deletion (19_del), 103 (43.8%) had exon 21 L858R mutations, and 19 (8.1%) had other mutation types, including exon 21 L861Q, exon 18 G719A/C, exon 20 S768I, and L858R/19_del double mutations. MET-positive expression was observed in 192 (81.7%) cases. There was no significant difference in baseline clinicopathological characteristics between MET positivity and MET negativity groups. Patients were stratified by different EGFR mutation subtypes. MET-positive patients in the L858R mutation subgroup had markedly shorter PFS and OS than MET-negative patients (median PFS: 13 versus 27.5 months, p < 0.001; median OS: 29 versus not reached, p = 0.008), but no significant difference was observed in the 19_del subgroup. Multivariate Cox regression analyses indicated that MET positivity was an independent predictor for poor PFS and OS in L858R subgroup (PFS: HR = 3.059, 95% CI 1.552-6.029, p = 0.001; OS: HR = 3.511, 95% CI 1.346-9.160, p = 0.010). Additionally, an inferior survival outcome of MET positivity was observed in the L858R mutation subgroup when treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy as the first-line regimen (median PFS: 13 versus 36.5 months, p < 0.001; median OS: 29 versus not reached, p = 0.012) but not with EGFR-TKI plus platinum doublet chemotherapy. CONCLUSIONS: MET positive expression was an independent predictor of poor outcomes in untreated EGFR L858R mutation advanced LUAD patients treated with first-line EGFR-TKI monotherapy.
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Adenocarcinoma del Pulmón , Receptores ErbB , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas c-met , Humanos , Masculino , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptores ErbB/genética , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/metabolismo , Pronóstico , Anciano , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/metabolismo , Adulto , Anciano de 80 o más Años , Supervivencia sin Progresión , Transición Epitelial-MesenquimalRESUMEN
Precision medicine has helped identify several tumor molecular aberrations to be treated with targeted therapies. These therapies showed substantial improvement in efficacy without excessive toxicity in patients with specific oncogenic drivers with advanced cancers. In metastatic lung cancers, the implementation of broad platforms for molecular tumor sequencing has helped oncology providers identify oncogenic drivers linked with better outcomes when treated upfront with targeted therapies. Mesenchymal-epithelial transition factor (MET) alterations are present in up to 60% of non-small cell lung cancer and are associated with a poor prognosis. Capmatinib and tepotinib are currently the only two approved targeted therapies by the U.S. Food and Drug Administration (FDA) for patients with MET exon 14 skipping mutation. Several agents are being developed to tackle an unmet need in patients with MET alterations. Some of these agents are being used in combination with EGFR targeted therapy to mitigate resistance to EGFR inhibitor. These agents are poised to provide new hope for these patients.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas c-met , Humanos , Antineoplásicos/uso terapéutico , 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/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Terapia Molecular Dirigida/métodos , Medicina de Precisión/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidoresRESUMEN
INTRODUCTION: Defining clinically relevant MET amplification levels in non-small cell lung cancer (NSCLC) remains challenging. We hypothesize that oncogene overlap and MET amplicon size decline with increase in MET plasma copy number (pCN), thus enriching for MET-dependent states. PATIENTS AND METHODS: We interrogated cell-free DNA NGS results of 16,782 patients with newly diagnosed advanced NSCLC to identify those with MET amplification as reported using Guardant360. Co-occurring genomic mutations and copy number alterations within each sample were evaluated. An exploratory method of adjusting for tumor fraction was also performed and amplicon size for MET was analyzed when available. RESULTS: MET amplification was detected in 207 (1.2%) of samples. pCN ranged from 2.1 to 52.9. Of these, 43 (20.8%) had an overlapping oncogenic driver, including 23 (11.1%) METex14 skipping or other MET mutations. The degree of (non-MET) oncogene overlap decreased with increases in pCN. Patients with MET pCN ≥ 2.7 had lower rates of overlapping drivers compared to those with MET pCN < 2.7 (6.1% vs. 16.3%, P = .033). None of the 7 patients with pCN > 6.7 had an overlapping driver. After adjusting for tumor fraction, adjusted pCN (ApCN) was also lower for those with overlapping drivers than those without (median ApCN 4.9 vs. 7.3, P =.024). There was an inverse relationship between amplicon size and pCN. CONCLUSIONS: We propose that a high MET pCN and/or ApCN, together with the absence of overlapping oncogenic drivers and small MET amplicon size, will enrich for patients most likely to derive benefit from MET targeted therapy.
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Carcinoma de Pulmón de Células no Pequeñas , Ácidos Nucleicos Libres de Células , ADN Tumoral Circulante , Neoplasias Pulmonares , Humanos , Carcinogénesis/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Ácidos Nucleicos Libres de Células/genética , ADN Tumoral Circulante/genética , Variaciones en el Número de Copia de ADN/genética , Exones , Neoplasias Pulmonares/patología , Oncogenes , Proteínas Proto-Oncogénicas c-met/genéticaRESUMEN
Esophageal squamous cell carcinoma (ESCC) is among the ten most frequent and deadly cancers, without effective therapies for most patients. More recently, drugs targeting deregulated growth factor signaling receptors have been developed, such as HGF-MET targeted therapy. We assessed MET and HGF genetic alterations and gene and protein expression profiles in ESCC patients from the Brazilian National Cancer Institute and publicly available datasets, as well as the intratumor heterogeneity of the alterations found. Our analyses showed that HGF and MET genetic alterations, both copy number and mutations, are not common in ESCC, affecting 5 and 6% of the cases, respectively. HGF showed a variable mRNA expression profile between datasets, with no alterations (GSE20347), downregulation (GSE45670), and upregulation in ESCC (our dataset and GSE75241). On the other hand, MET was found consistently upregulated in ESCC compared to non-tumor surrounding tissue, with median fold-changes of 5.96 (GSE20347), 3.83 (GSE45670), 6.02 (GSE75241), and 5.0 (our dataset). Among our patients, 84% of the tumors showed at least a two-fold increase in MET expression. This observation was corroborated by protein levels, with 55% of cases exhibiting positivity in 100% of the tumor cells. Intratumor heterogeneity was evaluated in at least four tumor biopsies from five patients and two cases showed a consistent increase in MET expression (at least two-fold) in all tumor samples. Our data suggested that HGF-MET signaling pathway was likely to be overactivated in ESCC, representing a potential therapeutic target, but eligibility for this therapy should consider intratumor heterogeneity.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias de Cabeza y Cuello , Brasil , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismoRESUMEN
Esophageal squamous cell carcinoma (ESCC) is among the ten most frequent and deadly cancers, without effective therapies for most patients. More recently, drugs targeting deregulated growth factor signaling receptors have been developed, such as HGF-MET targeted therapy. We assessed MET and HGF genetic alterations and gene and protein expression profiles in ESCC patients from the Brazilian National Cancer Institute and publicly available datasets, as well as the intratumor heterogeneity of the alterations found. Our analyses showed that HGF and MET genetic alterations, both copy number and mutations, are not common in ESCC, affecting 5 and 6% of the cases, respectively. HGF showed a variable mRNA expression profile between datasets, with no alterations (GSE20347), downregulation (GSE45670), and upregulation in ESCC (our dataset and GSE75241). On the other hand, MET was found consistently upregulated in ESCC compared to non-tumor surrounding tissue, with median fold-changes of 5.96 (GSE20347), 3.83 (GSE45670), 6.02 (GSE75241), and 5.0 (our dataset). Among our patients, 84% of the tumors showed at least a two-fold increase in MET expression. This observation was corroborated by protein levels, with 55% of cases exhibiting positivity in 100% of the tumor cells. Intratumor heterogeneity was evaluated in at least four tumor biopsies from five patients and two cases showed a consistent increase in MET expression (at least two-fold) in all tumor samples. Our data suggested that HGF-MET signaling pathway was likely to be overactivated in ESCC, representing a potential therapeutic target, but eligibility for this therapy should consider intratumor heterogeneity.
Asunto(s)
Humanos , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas de Esófago/genética , Neoplasias de Cabeza y Cuello , Brasil , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Línea Celular TumoralRESUMEN
BACKGROUND: Brigatinib is a potent ROS1 inhibitor. The existing data on its clinical activity in ROS1-rearranged non-small cell lung cancer (NSCLC) are limited to four cases. METHODS: Six patients with ROS1-rearranged advanced NSCLC treated with brigatinib were identified through search of the internal databases of four participating cancer centers. Four additional patients were selected by PubMed and Google Scholar search. The objective response rate (ORR), progression-free survival (PFS) (RECIST v.1.1), duration of treatment (DOT), and safety were assessed. RESULTS: Of eight patients evaluable for response assessment (crizotinib naive-1, crizotinib resistant -7), three patients demonstrated a partial response (ORR-37%). One crizotinib-naive patient had an ongoing response at 21.6 months. Of seven crizotinib-resistant patients, two patients demonstrated a partial response (ORR-29%), and one patient (14%) had stable disease. PFS, available in four crizotinib-resistant patients, was 7.6 + , 2.9, 2.0, and 0.4 months. In crizotinib-resistant patients, DOT was 9.7 + , 7.7 + , 7.6 + , 4.0, 2.0, 1.1, 0.4 months, and was not reported in two patients. Genomic profiling in one responder revealed no ROS1 alteration, suggesting that the response was attributable to "off-target" brigatinib activity. In two patients with progressive disease, genomic profiling demonstrated a cMET exon 14 mutation + KRAS G12A mutation in one case, and a persisting ROS1-CD74 fusion + TP53 K139N, FGFR2 E250G, ATM G2695D, and NF1 R2258Q mutations in the other. No grade 3-5 toxicity was observed. CONCLUSION: Brigatinib demonstrated modest activity in crizotinib-resistant ROS1-rearranged NSCLC. Its intracranial and systemic activity should be assessed in correlation with the underlying molecular mechanism of crizotinib resistance.
Our series is the first to describe brigatinib activity in ROS1-altered NSCLC. In crizotinib-resistant patients, ORR with brigatinib was 29%. PFS with brigatinib was 7.6+, 2.9, 2.0, and 0.4 months. DOT with brigatinib was 9.7+, 7.7+, 7.6+, 4.0, 2.0, 1.1, 0.4 months. The correlation between response and molecular resistance needs further exploration.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Organofosforados/uso terapéutico , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Pirimidinas/uso terapéutico , Anciano , Anciano de 80 o más Años , Antígenos CD/genética , Instituciones Oncológicas , Carcinoma de Pulmón de Células no Pequeñas/genética , Resistencia a Antineoplásicos , Femenino , Reordenamiento Génico/genética , Genes ras/genética , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Fusión Oncogénica , Compuestos Organofosforados/efectos adversos , Supervivencia sin Progresión , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/genética , Pirimidinas/efectos adversos , Sialiltransferasas/genéticaRESUMEN
In 2011 the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP) started a joint project to establish guidelines on biomarker testing in patients with advanced non-small-cell lung cancer (NSCLC) based on current evidence. As this field is constantly evolving, these guidelines have been updated, previously in 2012 and 2015 and now in 2019. Current evidence suggests that the mandatory tests to conduct in all patients with advanced NSCLC are for EGFR and BRAF mutations, ALK and ROS1 rearrangements and PD-L1 expression. The growing need to study other emerging biomarkers has promoted the routine use of massive sequencing (next-generation sequencing, NGS). The coordination of every professional involved and the prioritisation of the most suitable tests and technologies for each case remains a challenge.
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Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Quinasa de Linfoma Anaplásico/genética , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , ADN Tumoral Circulante , Receptores ErbB/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Biopsia Líquida , Neoplasias Pulmonares/genética , Glicoproteínas de Membrana/genética , Células Neoplásicas Circulantes , Reacción en Cadena de la Polimerasa , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-ret/genética , Receptor ErbB-2/genética , Receptor trkA/genética , Receptor trkB/genética , Receptor trkC/genética , Sociedades Médicas , EspañaRESUMEN
Fridericia platyphylla (Cham.) L.G. Lohmann (FP) has cytotoxic, anti-inflammatory, and analgesic properties. We aimed to characterize the cytotoxic and antiproliferative effects of FP extract on normal (GAS) and tumor-derived (ACP02 and HepG2) cell lines. The effective concentrations (EC50s) by tetrazolium bromide assay (MTT) were 56.16, 43.68, and 42.57 µg mL-1 and 69.38, 41.73, and 52.39 µg mL-1 by neutral red assay for GAS, ACP02, and HepG2 cells, respectively. The extract decreased nuclear division indices, which was not reflected in cell proliferation curves. Flow cytometric analyses showed that even 30 µg mL-1 extract (shown to be noncytotoxic by MTT assay) increased the sub-G1 population, indicating cell death due to apoptosis and necrosis. A cytokinesis-block micronucleus cytome assay showed that 30 µg mL-1 of the extract increased the frequency of nuclear buds in tumor cells. Real-time quantitative polymerase chain reaction showed CCND1 upregulation in doxorubicin-treated GAS cells and BCL-XL, BIRC5, and MET downregulation in 5 or 30 µg mL-1 in FP extract-treated ACP02 cells. In conclusion, FP extract modulated apoptosis- and cell cycle-related genes and presented selective cytotoxicity toward tumor cells that deserves further investigation by testing other cell types. Our results demonstrated that even medicinal plants exert adverse effects depending on the extract concentrations used and tissues investigated.
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Bignoniaceae/química , Extractos Vegetales/farmacología , Raíces de Plantas/química , Neoplasias Gástricas/tratamiento farmacológico , Survivin/metabolismo , Proteína bcl-X/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Necrosis , Extractos Vegetales/química , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Especies Reactivas de Oxígeno , Survivin/genética , Proteína bcl-X/genéticaRESUMEN
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) represents a paradigm shift in the treatment of non-small cell lung cancer (NSCLC) patients and has been the first-line therapy in clinical practice. While erlotinib, gefitinib and afatinib have achieved superior efficacy in terms of progression-free survival and overall survival compared with conventional chemotherapy in NSCLC patients, most people inevitably develop acquired resistance to them, which presents another challenge in the treatment of NSCLC. The mechanisms of acquired resistance can be classified as three types: target gene mutation, bypass signaling pathway activation and histological transformation. And the most common mechanism is T790M which accounts for approximately 50% of all subtypes. Many strategies have been explored to overcome the acquired resistance to EGFR TKI. Continuation of EGFR TKI beyond progressive disease is confined to patients in asymptomatic stage when the EGFR addiction is still preserved in some subclones. While the combination of EGFR TKI and chemotherapy or other targeted agents has improved the survival benefit in EGFR TKI resistant patients, there are controversies within them. The next-generation EGFR TKI and immunotherapy represent two novel directions for overcoming acquired resistance and have achieved promising efficacy. Liquid biopsy provides surveillance of the EGFR mutation by disclosing the entire genetic landscape but tissue biopsy is still indispensable because of the considerable rate of false-negative plasma.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Acrilamidas/uso terapéutico , Afatinib/uso terapéutico , Compuestos de Anilina/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Transformación Celular Neoplásica , Fosfatidilinositol 3-Quinasa Clase I/genética , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Quimioterapia Combinada/métodos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib/uso terapéutico , Gefitinib/uso terapéutico , Humanos , Inmunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-met/genética , Quinazolinonas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/genética , Receptor IGF Tipo 1/genética , Transducción de Señal , Tirosina Quinasa del Receptor AxlRESUMEN
BACKGROUND: Cemento-ossifying fibroma (COF) is a benign fibro-osseous neoplasm of uncertain pathogenesis, and its treatment results in morbidity. MicroRNAs (miRNA) are small non-coding RNAs that regulate gene expression and may represent therapeutic targets. The purpose of the study was to generate a comprehensive miRNA profile of COF compared to normal bone. Additionally, the most relevant pathways and target genes of differentially expressed miRNA were investigated by in silico analysis. METHODS: Nine COF and ten normal bone samples were included in the study. miRNA profiling was carried out by using TaqMan® OpenArray® Human microRNA panel containing 754 validated human miRNAs. We identified the most relevant miRNAs target genes through the leader gene approach, using STRING and Cytoscape software. Pathways enrichment analysis was performed using DIANA-miRPath. RESULTS: Eleven miRNAs were downregulated (hsa-miR-95-3p, hsa-miR-141-3p, hsa-miR-205-5p, hsa-miR-223-3p, hsa-miR-31-5p, hsa-miR-944, hsa-miR-200b-3p, hsa-miR-135b-5p, hsa-miR-31-3p, hsa-miR-223-5p and hsa-miR-200c-3p), and five were upregulated (hsa-miR-181a-5p, hsa-miR-181c-5p, hsa-miR-149-5p, hsa-miR-138-5p and hsa-miR-199a-3p) in COF compared to normal bone. Eighteen common target genes were predicted, and the leader genes approach identified the following genes involved in human COF: EZH2, XIAP, MET and TGFBR1. According to the biology of bone and COF, the most relevant KEGG pathways revealed by enrichment analysis were proteoglycans in cancer, miRNAs in cancer, pathways in cancer, p53-, PI3K-Akt-, FoxO- and TGF-beta signalling pathways, which were previously found to be differentially regulated in bone neoplasms, odontogenic tumours and osteogenesis. CONCLUSION: miRNA dysregulation occurs in COF, and EZH2, XIAP, MET and TGFBR1 are potential targets for functional analysis validation.
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Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Fibroma Osificante/genética , Fibroma Osificante/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , MicroARNs/genética , Adolescente , Adulto , Biología Computacional , Regulación hacia Abajo , Proteína Potenciadora del Homólogo Zeste 2/genética , Femenino , Factores de Transcripción Forkhead/metabolismo , Estudios de Asociación Genética , Humanos , Masculino , MicroARNs/clasificación , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Tumores Odontogénicos , Osteogénesis , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-met/genética , ARN no Traducido , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Adulto JovenRESUMEN
PURPOSE: Aberrant activation of MET as a result of exon 14-skipping (METex14) mutations or gene amplification is an oncogenic mechanism in non-small cell lung carcinoma (NSCLC) and a potential therapeutic target. The purpose of this study was to characterize MET alterations in a cohort of NSCLC patients treated with surgery. METHODS AND PATIENTS: 157 NSCLCs of various histopathologies, including pulmonary sarcomatoid carcinomas (PSC), were tested for MET alterations. METex14 mutations, MET copy number alterations and the levels of MET protein were determined by Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry, respectively. Concurrent alterations of other important cancer genes and immunostaining of the downstream effector, phopho-S6, were also determined. RESULTS: METex14 mutations and MET amplification were detected in seven tumors. MET genetic alterations were found predominantly in the lung adenocarcinoma (ADC) and PSC histopathologies. High levels of MET protein were found in most MET-amplified tumors, but not in all METex14-mutated tumors. Strong phopho-S6 staining was observed in about half of the MET-activated tumors. One tumor with METex14 exhibited concurrent ERBB2 amplification. CONCLUSIONS: MET activation, by either METex14 mutations or amplification, is characteristic of a subset of early stage NSCLCs and may coexist with ERBB2 amplification. This may have potential therapeutic implications. The presence of METex14 mutations was associated with low levels of MET protein, which may limit the use of total MET immunostaining as a marker for preselecting patients for MET-targeted therapies.
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Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Amplificación de Genes , Pruebas Genéticas , Neoplasias Pulmonares/genética , Mutación , Proteínas Proto-Oncogénicas c-met/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Exones , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMEN
AIMS: To identify calcifying epithelial odontogenic tumour (CEOT) mutations in oncogenes and tumour suppressor genes. METHODS: A panel of 50 genes commonly mutated in cancer was sequenced in CEOT by next-generation sequencing. Sanger sequencing was used to cover the region of the frameshift deletion identified in one sample. RESULTS: Missense single nucleotide variants (SNVs) with minor allele frequency (MAF) <1% were detected in PTEN, MET and JAK3. A frameshift deletion in CDKN2A occurred in association with a missense mutation in the same gene region, suggesting a second hit in the inactivation of this gene. APC, KDR, KIT, PIK3CA and TP53 missense SNVs were identified; however, these are common SNVs, showing MAF >1%. CONCLUSION: CEOT harbours mutations in the tumour suppressor PTEN and CDKN2A and in the oncogenes JAK3 and MET. As these mutations occurred in only one case each, they are probably not driver mutations for these tumours.
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Tumores Odontogénicos/genética , Oncogenes/genética , Neoplasias Cutáneas/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Inhibidor p18 de las Quinasas Dependientes de la Ciclina , Femenino , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Janus Quinasa 3/genética , Masculino , Proteínas de la Membrana/genética , Microdisección , Persona de Mediana Edad , Mutación , Mutación Missense , Tumores Odontogénicos/patología , Fosfohidrolasa PTEN/genética , Proteínas Proto-Oncogénicas c-met/genética , Análisis de Secuencia de ADN , Neoplasias Cutáneas/patologíaRESUMEN
Activation of the MET proto-oncogene (MET) highly sensitive to MET inhibition has recently been described in NSCLC through two mechanisms: high-level amplification of the MNNG HOS Transforming gene (MET) (usually expressed relative to the chromosome 7 centromere [CEP7] when using fluorescence in situ hybridization) and exon 14 alterations. As partial overlap of these biomarkers occurs, whether one is purely a surrogate for the other or both can represent true oncogenic driver states continues to be explored. Cases of MET inhibitor-sensitive NSCLC harboring exon 14 alterations without coincident amplification have already been described. Here we report two cases of MET inhibitor-sensitive NSCLC harboring high-level MET amplification (MET/CEP7 ratio ≥5) without coincident exon 14 alterations, suggesting that these two methods of MET activation can produce independent MET-addicted states in NSCLC. Molecular profiling designed to capture all cases of potentially MET-addicted NSCLC should address both activation mechanisms.
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Adenocarcinoma/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Exones/genética , Amplificación de Genes , Proteínas Proto-Oncogénicas c-met/genética , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Anciano , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Crizotinib , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proto-Oncogenes MasRESUMEN
Recent studies confirmed a critical importance of c-Met signaling for liver regeneration by modulating redox balance. Here we used liver-specific conditional knockout mice (MetKO) and a nutritional model of hepatic steatosis to address the role of c-Met in cholesterol-mediated liver toxicity. Liver injury was assessed by histopathology and plasma enzymes levels. Global transcriptomic changes were examined by gene expression microarray, and key molecules involved in liver damage and lipid homeostasis were evaluated by Western blotting. Loss of c-Met signaling amplified the extent of liver injury in MetKO mice fed with high-cholesterol diet for 30days as evidenced by upregulation of liver enzymes and increased synthesis of total bile acids, aggravated inflammatory response and enhanced intrahepatic lipid deposition. Global transcriptomic changes confirmed the enrichment of networks involved in steatosis and cholestasis. In addition, signaling pathways related to glutathione and lipid metabolism, oxidative stress and mitochondria dysfunction were significantly affected by the loss of c-Met function. Mechanistically, exacerbation of oxidative stress in MetKO livers was corroborated by increased lipid and protein oxidation. Western blot analysis further revealed suppression of Erk, NF-kB and Nrf2 survival pathways and downstream target genes (e.g. cyclin D1, SOD1, gamma-GCS), as well as up-regulation of proapoptotic signaling (e.g. p53, caspase 3). Consistent with the observed steatotic and cholestatic phenotype, nuclear receptors RAR, RXR showed increased activation while expression levels of CAR, FXR and PPAR-alpha were decreased in MetKO. Collectively, our data provide evidence for the critical involvement of c-Met signaling in cholesterol and bile acids toxicity.
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Colestasis Intrahepática/inducido químicamente , Colestasis Intrahepática/metabolismo , Hepatocitos/efectos de los fármacos , Lípidos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Colesterol en la Dieta/toxicidad , Glutatión/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Peroxidación de Lípido , Pruebas de Función Hepática , Ratones , Ratones Noqueados , Transducción de SeñalRESUMEN
Copy number alterations (CNA) are one of the driving mechanisms of glioma tumorigenesis, and are currently used as important biomarkers in the routine setting. Therefore, we performed CNA profiling of 65 astrocytomas of distinct malignant grades (WHO grade I-IV) of Brazilian origin, using array-CGH and microsatellite instability analysis (MSI), and investigated their correlation with TERT and IDH1 mutational status and clinico-pathological features. Furthermore, in silico analysis using the Oncomine database was performed to validate our findings and extend the findings to gene expression level. We found that the number of genomic alterations increases in accordance with glioma grade. In glioblastomas (GBM), the most common alterations were gene amplifications (PDGFRA, KIT, KDR, EGFR, and MET) and deletions (CDKN2A and PTEN) Log-rank analysis correlated EGFR amplification and/or chr7 gain with better survival of the patients. MSI was observed in 11% of GBMs. A total of 69% of GBMs presented TERT mutation, whereas IDH1 mutation was most frequent in diffuse (85.7%) and anaplastic (100%) astrocytomas. The combination of 1p19q deletion and TERT and IDH1 mutational status separated tumor groups that showed distinct age of diagnosis and outcome. In silico validation pointed to less explored genes that may be worthy of future investigation, such as CDK2, DMRTA1, and MTAP Herein, using an extensive integrated analysis, we indicated potentially important genes, not extensively studied in gliomas, that could be further explored to assess their biological and clinical impact in astrocytomas.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Proteínas de Neoplasias/genética , Adolescente , Adulto , Anciano , Astrocitoma/diagnóstico , Astrocitoma/metabolismo , Astrocitoma/patología , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Brasil , Niño , Hibridación Genómica Comparativa , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Inhibidor p18 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p18 de las Quinasas Dependientes de la Ciclina/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Glioblastoma/diagnóstico , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Clasificación del Tumor , Proteínas de Neoplasias/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Telomerasa/genética , Telomerasa/metabolismo , Análisis de Matrices Tisulares , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Hepatocellular cancer (HCC) remains a significant therapeutic challenge due to its poorly understood molecular basis. In the current study, we investigated two independent cohorts of 249 and 194 HCC cases for any combinatorial molecular aberrations. Specifically we assessed for simultaneous HMET expression or hMet activation and catenin ß1 gene (CTNNB1) mutations to address any concomitant Met and Wnt signaling. To investigate cooperation in tumorigenesis, we coexpressed hMet and ß-catenin point mutants (S33Y or S45Y) in hepatocytes using sleeping beauty transposon/transposase and hydrodynamic tail vein injection and characterized tumors for growth, signaling, gene signatures, and similarity to human HCC. Missense mutations in exon 3 of CTNNB1 were identified in subsets of HCC patients. Irrespective of amino acid affected, all exon 3 mutations induced similar changes in gene expression. Concomitant HMET overexpression or hMet activation and CTNNB1 mutations were evident in 9%-12.5% of HCCs. Coexpression of hMet and mutant-ß-catenin led to notable HCC in mice. Tumors showed active Wnt and hMet signaling with evidence of glutamine synthetase and cyclin D1 positivity and mitogen-activated protein kinase/extracellular signal-regulated kinase, AKT/Ras/mammalian target of rapamycin activation. Introduction of dominant-negative T-cell factor 4 prevented tumorigenesis. The gene expression of mouse tumors in hMet-mutant ß-catenin showed high correlation, with subsets of human HCC displaying concomitant hMet activation signature and CTNNB1 mutations. CONCLUSION: We have identified cooperation of hMet and ß-catenin activation in a subset of HCC patients and modeled this human disease in mice with a significant transcriptomic intersection; this model will provide novel insight into the biology of this tumor and allow us to evaluate novel therapies as a step toward precision medicine. (Hepatology 2016;64:1587-1605).
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Mutación Puntual , Proteínas Proto-Oncogénicas c-met/genética , beta Catenina/genética , Animales , Regulación Neoplásica de la Expresión Génica , Masculino , Ratones , Modelos BiológicosRESUMEN
Breast Cancer (BC) is a highly prevalent disease. A woman living in the United States has a 12.3% lifetime risk of being diagnosed with breast cancer [1]. It is the most common female cancer and the second most common cause of cancer death in women [2]. Of note, amplification or overexpression of Human Epidermal Receptor 2 (HER2) oncogene is present in approximately 18 to 20% of primary invasive breast cancers, and until personalized therapy became available for this specific BC subtype, the worst rates of Overall Survival (OS) and Recurrence-Free Survival (RFS) were observed in the HER2+ BC cohort, compared to all other types, including triple negative BC (TNBC) [3].HER2 is a member of the epidermal growth factor receptor (EGFR) family. Other family members include EGFR or HER1, HER3 and HER4. HER2 can form heterodimers with any of the other three receptors, and is considered to be the preferred dimerization partner of the other HER or ErbB receptors [4]. Phosphorylation of tyrosine residues within the cytoplasmic domain is the result of receptor dimerization and culminates into initiation of a variety of signalling pathways involved in cellular proliferation, transcription, motility and apoptosis inhibition [5].In addition to being an important prognostic factor in women diagnosed with BC, HER2 overexpression also identifies those patients who benefit from treatment with agents that target HER2, such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and small molecules tyrosine kinase inhibitors of HER2 [6, 11, 127].In fact, trastuzumab altered the natural history of patients diagnosed with HER2+ BC, both in early and metastatic disease setting, in a major way [8-10]. Nevertheless, there are many women that will eventually develop metastatic disease, despite being treated with anti-HER2 therapy in the early disease setting. Moreover, advanced tumors may reach a point where no anti-HER2 treatment will achieve disease control, including recently approved drugs, such as T-DM1.This review paper will concentrate on major biological pathways that ultimately lead to resistance to anti-HER2 therapies in BC, summarizing their mechanisms. Strategies to overcome this resistance, and the rationale involved in each tactics to revert this scenario will be presented to the reader.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Animales , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Fosfatidilinositol 3-Quinasa Clase I/genética , Femenino , Humanos , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Receptor IGF Tipo 1 , Receptores de Somatomedina/antagonistas & inhibidores , Receptores de Somatomedina/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Resultado del Tratamiento , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismoRESUMEN
INTRODUCTION: Molecular targets are emerging rapidly and the development of clinical tests that simultaneously screen for multiple targets has become especially important. We assessed the gene expression levels of three known targets in advanced gastric cancer, epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and N-methyl-N-nitrosoguanidine human osteosarcoma transforming gene (MET), using the nCounter® assay (NanoString Technologies, Seattle, WA, USA) and compared these results with protein overexpression, detected by immunohistochemistry, to evaluate the performance of this new technology. METHODS: We investigated 42 formalin-fixed, paraffin-embedded tumor samples from patients with gastric cancer. A NanoString-based assay containing a 522 kinase gene panel was investigated. We analyzed the correlations between immunohistochemical findings and kinase gene expression levels of EGFR, HER2 and MET to validate this assay. RESULTS: EGFR, HER2, and MET overexpression were observed in 7 (16.6 %), 5 (11.9 %), and 3 (7.1 %) cases, respectively. For EGFR, HER2, and MET, the concordance rates between the NanoString-based assay results and the immunohistochemistry methods were 83.3, 97.6, and 100 %, respectively. Relative to immunohistochemistry findings, the NanoString-based assay sensitivities and specificities were 85.7 and 82.8 % for EGFR, 100 and 97.2 % for HER2, and 100 and 100 % for MET, respectively. CONCLUSIONS: We found a high concordance between immunohistochemistry- and nCounter-based assessments of EGFR, HER2, and MET in advanced gastric cancer. Judged against immunohistochemistry results, the NanoString assay had high sensitivities and high specificities. These results suggest that the nCounter assay provides a reliable, high-throughput assay to simultaneously screen for the overexpression of several target proteins.