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1.
Nat Commun ; 11(1): 5017, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024122

RESUMO

The survival and recurrence of residual tumor cells following therapy constitutes one of the biggest obstacles to obtaining cures in breast cancer, but it remains unclear how the clonal composition of tumors changes during relapse. We use cellular barcoding to monitor clonal dynamics during tumor recurrence in vivo. We find that clonal diversity decreases during tumor regression, residual disease, and recurrence. The recurrence of dormant residual cells follows several distinct routes. Approximately half of the recurrent tumors exhibit clonal dominance with a small number of subclones comprising the vast majority of the tumor; these clonal recurrences are frequently dependent upon Met gene amplification. A second group of recurrent tumors comprises thousands of subclones, has a clonal architecture similar to primary tumors, and is dependent upon the Jak/Stat pathway. Thus the regrowth of dormant tumors proceeds via multiple routes, producing recurrent tumors with distinct clonal composition, genetic alterations, and drug sensitivities.


Assuntos
Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Animais , Linhagem Celular Tumoral , Crizotinibe/farmacologia , Doxiciclina/farmacologia , Transição Epitelial-Mesenquimal/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Camundongos Nus , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Receptor ErbB-2/genética , Análise de Célula Única , Ensaios Antitumorais Modelo de Xenoenxerto
2.
N Engl J Med ; 383(10): 944-957, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32877583

RESUMO

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. METHODS: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. RESULTS: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. CONCLUSIONS: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imidazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Triazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Edema/induzido quimicamente , Éxons , Feminino , Dosagem de Genes , Humanos , Imidazóis/efeitos adversos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/genética , Triazinas/efeitos adversos
3.
Life Sci ; 261: 118316, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32835698

RESUMO

AIMS: Deubiquitinase ubiquitin-specific protease 33 (USP33) is abnormally expressed in various tumors and participates in tumor progression. However, the expression and biological role of USP33 in hepatocellular carcinoma (HCC) are still unclear. MAIN METHODS: We performed immunohistochemistry, western blotting, and qRT-PCR analysis to determine the expression of USP33 in HCC. We then analyzed the effects of USP33 expression on the prognosis of HCC. The roles of USP33 in regulating HCC cell migration and invasion were further explored in vitro. Animal studies were performed to investigate the effects of USP33 on tumor metastasis. RNA sequencing and luciferase reporter and immunofluorescence assays were used to identify the activation of the specificity protein 1 (SP1)/c-Met axis. KEY FINDINGS: Here, for the first time, we reported an abnormal increase in the expression of USP33 in HCC tissues and that USP33 may act as a prognostic biomarker for HCC patients. We found that USP33 knockdown inhibited the invasion and metastasis in HCC cells both in vitro and in vivo, which was partly dependent on c-Met. Further investigations revealed that USP33 regulated c-Met expression by enhancing the protein stability of the transcription factor SP1 in HCC cells. Mechanistically, USP33 directly bound SP1 and decreased its ubiquitination, thereby upregulating c-Met expression. SIGNIFICANCE: Our results reveal that USP33 acts as the deubiquitinating enzyme of SP1 and contributes to HCC invasion and metastasis through activation of the SP1/c-Met axis. These data indicate a previously unknown function of USP33, which may provide potential targets for the treatment of HCC patients.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-met/genética , Ubiquitina Tiolesterase/genética , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/genética , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Prognóstico , Fator de Transcrição Sp1/metabolismo , Regulação para Cima
4.
Brain Tumor Pathol ; 37(4): 136-144, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32761533

RESUMO

Oncogenic gene fusions have been reported in diffuse gliomas and may serve as potential therapeutic targets. Here, using next-generation sequencing analysis (Illumina TruSight Tumor 170 panel), we analyzed a total of 356 diffuse gliomas collected from 2017 to 2019 to evaluate clinical, pathological, and genetic features of gene fusion. We found 53 cases of glioblastomas harboring the following oncogenic gene fusions: MET (n = 18), EGFR (n = 14), FGFR (n = 12), NTRK (n = 5), RET (n = 2), AKT3 (n = 1), and PDGFRA fusions (n = 1). Gene fusions were consistently observed in both IDH-wildtype and IDH-mutant glioblastomas (8.8% and 9.4%, p = 1.000). PTPRZ1-MET fusion was the only fusion that genetically resembled secondary glioblastomas (i.e., high frequency of IDH mutation, ATRX loss, TP53 mutation, and absence of EGFR amplification), whereas other gene fusion types were similar to primary glioblastomas (i.e., high frequency of IDH-wildtype, TERT mutation, EGFR amplification, and PTEN mutation). In IDH-wildtype glioblastoma patients, multivariable analysis revealed that the PTPRZ1-MET fusion was associated with poor progression-free survival (HR [95% CI]: 5.42 (1.72-17.05), p = 0.004). Additionally, we described two novel cases of CCDC6-RET fusion in glioma. Collectively, our findings indicate that targetable gene fusions are associated with aggressive biological behavior and can aid the clinical treatment strategy for glioma patients.


Assuntos
Neoplasias Encefálicas/genética , Fusão Gênica/genética , Estudos de Associação Genética , Glioblastoma/genética , Glioma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Proteínas do Citoesqueleto/genética , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioma/mortalidade , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-ret/genética , Taxa de Sobrevida
5.
Nat Rev Nephrol ; 16(8): 435-451, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32561872

RESUMO

The treatment landscape of metastatic renal cell carcinoma (RCC) has been revolutionized over the past two decades, bringing forth an era in which more than a dozen therapeutic agents are now available to treat patients. As a consequence, personalized care has become a critical part of developing effective treatment guidelines and improving patient outcomes. One of the most important emerging aspects of precision medicine in cancer is matching patients and treatments based on the genomic characteristics of an individual and their tumour. Despite the lack of a single genomic predictor of treatment response or prognostication feature in RCC, emerging research suggests that the identification of such markers remains promising. Mutations in VHL and alterations in its downstream pathways are the mainstay of RCC development and progression. However, the predictive value of VHL mutations has been questioned. Further research has examined mutations in genes involved in chromosome remodelling (for example, PBRM1, BAP1 and SETD2), DNA methylation and DNA damage repair, all of which have been associated with clinical outcomes. Here, we provide a comprehensive overview of genomic evidence in the context of RCC and its potential predictive and prognostic value.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/genética , Genômica , Neoplasias Renais/genética , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Metilação de DNA/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Neurofibromina 2/genética , PTEN Fosfo-Hidrolase/genética , Medicina de Precisão , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Telomerase/genética , Fatores de Transcrição/genética , Transcriptoma , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética
6.
Rev Mal Respir ; 37(6): 488-491, 2020 Jun.
Artigo em Francês | MEDLINE | ID: mdl-32430158

RESUMO

INTRODUCTION: Lung cancer displays molecular anomalies for which targeted therapies are the standard first line treatment. The EGFR mutation is present in 10% of cases of non-small cell lung cancer in Caucasians. MET amplification associated with an exon 19 EGFR mutation has been identified though it is usually regarded as a mechanism of resistance. CASE REPORT: We report the case of a 74-year-old never-smoking woman who was diagnosed with stage IV bronchial adenocarcinoma showing both EGFR mutation and MET amplification. Initial treatment with gefitinib did not control the disease. Platinum-based chemotherapy with pemetrexed maintenance allowed a temporary response. Treatment with durvalumab for 27 months was associated with disease stability. Single agent crizotinib was associated with a slight response followed by progression. The concomitant introduction of crizotinib and gefitinib led to a spectacular and durable response with no safety issues. CONCLUSIONS: This case highlights the efficacy of concomitant treatment in a patient with two oncogenic drivers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/administração & dosagem , Cloridrato de Erlotinib/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/genética , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Feminino , Amplificação de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Mutação , Resultado do Tratamento
7.
Virchows Arch ; 477(1): 33-45, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32447492

RESUMO

Biliary tract carcinomas are divided into intrahepatic, perihilar, distal extrahepatic cholangiocarcinomas, and gallbladder adenocarcinomas. Therapies targeting ROS1, ALK, MET, and HER2 alterations are currently evaluated in clinical trials. We assessed ROS1 and ALK translocations/amplifications as well as MET and HER2 amplifications for each tumor subtype by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) in 73 intrahepatic, 40 perihilar bile duct, 36 distal extrahepatic cholangiocarcinomas, and 45 gallbladder adenocarcinomas (n = 194). By FISH, we detected targetable alterations in 5.2% of cases (n = 10): HER2 and MET amplifications were found in 4.1% (n = 8) and 1.0% (n = 2), respectively. The HER2-amplified cases were mostly gallbladder adenocarcinomas (n = 5). The MET- and HER2-amplified cases were all positive by IHC. Fourteen cases without MET amplification were positive by IHC, whereas HER2 over-expression was detected by IHC only in HER2-amplified cases. We detected no ALK or ROS1 translocation or amplification. Several alterations were consistent with aneuploidy: 24 cases showed only one copy of ROS1 gene, 4 cases displayed a profile of chromosomal instability, and an over-representation of centromeric alpha-satellite sequences was found in five cases. We confirm a relatively high rate of HER2 amplifications in gallbladder adenocarcinomas and the efficacy of IHC to screen these cases. Our results also suggest the value of IHC to screen MET amplification. Contrary to initial publications, ROS1 rearrangements seem to be very rare in biliary tract adenocarcinomas. We confirm a relatively high frequency of aneuploidy and chromosomal instability and reveal the over-representation of centromeric alpha-satellite sequences in intrahepatic cholangiocarcinomas.


Assuntos
Adenocarcinoma/genética , Rearranjo Gênico/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptor ErbB-2/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Quinase do Linfoma Anaplásico/genética , Sistema Biliar/patologia , Humanos , Hibridização in Situ Fluorescente/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-met/genética
8.
N Engl J Med ; 383(10): 931-943, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32469185

RESUMO

BACKGROUND: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS: Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Edema/induzido quimicamente , Éxons , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/genética , Piridazinas/efeitos adversos , Pirimidinas/efeitos adversos
9.
Gene ; 754: 144811, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32464246

RESUMO

Renal cell carcinoma (RCC) is one of the most common tumors of the urinary system, seriously impacting public health. CircRNAs have been indicated as potentially critical mediators in tumorigenesis and cancer progression. However, their specific role in the metastasis of RCC remains unclear. In present study, we identified that miR-130a-3p presented aberrantly low-level in RCC cells. Furthermore, it was demonstrated that upregulated miR-130a-3p suppressed the proliferation and migration of cell and promoted cell apoptosis in RCC. Then we predicted the underlyingly upstream modulator of miR-130a-3p was a novel circRNA hsa_circ_0054537, which exhibited dysregulated in RCC cells. Subsequently, we confirmed the direct interaction between hsa_circ_0054537 and miR-130a-3p by RNA pulldown assay. Additionally, luciferase assay confirmed the correlation between hsa_circ_0054537 and miR-130a-3p at the transcriptional level. We also found hsa_circ_0054537 could affect the tumorigenesis through binding to miR-130a-3p competitively. In addition, we identified the target of miR-130a-3p was oncogene cMet, which could be co-controlled by hsa_circ_0054537 and miR-130a-3p. In conclusion, we demonstrated that circRNA hsa_circ_0054537 functioned as a competitive endogenous RNA to regulate cMet expression via sponging miR-130a-3p in renal cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/patologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Circular/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinogênese , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Proliferação de Células , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Proteínas Proto-Oncogênicas c-met/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Int J Clin Oncol ; 25(8): 1450-1458, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32440811

RESUMO

MET activation includes gene mutation, amplification, and protein overexpression. Clinical evidence suggests that MET activation is both a primary oncogenic driver in lung cancer, and a secondary driver after acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Several small molecule TKIs have already shown to be effective in the MET pathway. However, the activation form and the diagnostic criteria of MET oncogene are still controversial, especially in patients resistant to EGFR TKIs or ALK TKIs. With the development of new MET inhibitors, a quantity of emerging trials has focused on the mechanism of acquired resistance to MET TKIs and therapeutic strategies after resistance.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/metabolismo , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Transdução de Sinais/efeitos dos fármacos
11.
Cancer Treat Rev ; 87: 102022, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32334240

RESUMO

Dysregulated activation of the MET tyrosine kinase receptor is implicated in the development of solid tumors and can arise through several mechanisms, including gene amplification, overexpression of the receptor and/or its ligand hepatocyte growth factor (HGF), and the acquisition of activating mutations. The most common activating mutations cause exon 14 to be skipped during MET mRNA splicing. This in-frame deletion, known as MET exon 14, results in production of a shortened receptor that lacks a juxtamembrane domain but retains affinity for HGF. However, the negative regulatory function located within this protein sequence is lost, leading to receptor accumulation on the cell surface and prolonged activation by HGF. MET mutations causing exon 14 skipping appear to be true oncogenic drivers and occur in patients and tumors with distinct characteristics. Increasing evidence suggests that tumors carrying such mutations are sensitive to MET inhibition, raising the hope that selective MET inhibitors will provide patients with optimal anticancer activity with minimal toxicity. We discuss the prospects for selective MET inhibitors in the treatment of non-small cell lung cancer harboring MET exon 14 skipping.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Éxons , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Oncogene ; 39(17): 3522-3540, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32111984

RESUMO

Metastasis is a major cause of high recurrence and poor survival of patients with colorectal cancer (CRC), although the mechanisms associated with this process remain poorly understood. In this study, we report a novel mechanism by which SOX13 promotes CRC metastasis by transactivating SNAI2 and c-MET. SOX13 overexpression was significantly correlated with more aggressive clinicopathological features of CRC and indicated poor prognosis in two independent cohorts of CRC patients (cohort I, n = 363; cohort II, n = 390). Overexpression of SOX13-promoted CRC migration, invasion, and metastasis, whereas SOX13 downregulation caused the opposite effects. Further mechanistic investigation identified SNAI2 and MET as important target genes of SOX13 using serial deletion and site-directed mutagenesis luciferase reporter and chromatin immunoprecipitation (ChIP) assays, as well as functional complementation analyses. In addition, SOX13 was shown to be a direct target of HGF/STAT3 signaling, and the c-MET inhibitor crizotinib blocked the HGF/STAT3/SOX13/c-MET axis, significantly inhibiting SOX13-mediated CRC migration, invasion and metastasis. Moreover, in clinical CRC tissues, SOX13 expression was positively correlated with the expression of SNAI2, c-MET, and HGF. CRC patients with positive coexpression of SOX13/SNAI2, SOX13/c-MET, or HGF/SOX13 exhibited a worse prognosis. In summary, SOX13 is a promising prognostic biomarker in patients with CRC, and blocking the HGF/STAT3/SOX13/c-MET axis with crizotinib could be a new therapeutic strategy to prevent SOX13-mediated CRC metastasis.


Assuntos
Autoantígenos/metabolismo , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-met/biossíntese , Fatores de Transcrição SOXD/metabolismo , Fatores de Transcrição da Família Snail/biossíntese , Ativação Transcricional , Animais , Autoantígenos/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-met/genética , Fatores de Transcrição SOXD/genética , Fatores de Transcrição da Família Snail/genética
13.
Med Oncol ; 37(4): 24, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32166604

RESUMO

Lenvatinib is a long-awaited alternative to sorafenib for the first-line targeted therapy of patients with advanced hepatocellular carcinoma (HCC). However, resistance to lenvatinib has also become a major obstacle to improving the prognosis of HCC patients. The underlying molecular mechanisms contributing to lenvatinib resistance in HCC are largely unknown. HGF/c-MET axis activation is related to tumor progression and several hallmarks of cancer and is considered as the key contributor to drug resistance. In the present study, we focused on the role of the HGF/c-MET axis in mediating lenvatinib resistance in HCC cells. We showed that HGF reduced the antiproliferative, proapoptotic, and anti-invasive effects of lenvatinib on HCC cells with high c-MET expression but did not significantly affect HCC cells with low c-MET expression. The c-MET inhibitor PHA-665752 rescued HCC cells from HGF-induced lenvatinib resistance. Furthermore, HGF/c-MET activated the downstream PI3K/AKT and MAPK/ERK pathways and promoted epithelial-mesenchymal transition (EMT) in HCC cells. Collectively, our results suggested that combining lenvatinib treatment with a c-MET inhibitor may improve its systemic therapeutic efficacy in HCC patients with high c-MET expression.


Assuntos
Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fator de Crescimento de Hepatócito/metabolismo , Neoplasias Hepáticas/metabolismo , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Quinolinas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Indóis/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia
14.
Nat Commun ; 11(1): 1556, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32214092

RESUMO

c-MET receptors are activated in cancers through genomic events like tyrosine kinase domain mutations, juxtamembrane splicing mutation and amplified copy numbers, which can be inhibited by c-MET small molecule inhibitors. Here, we discover that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables METN375S to interact with HER2 in a ligand-independent fashion. The resultant METN375S/HER2 dimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis. Accordingly, HER2 blockers, but not c-MET inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing METN375S. These results establish METN375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Fenótipo , Fosforilação/efeitos dos fármacos , Polimorfismo Genético , Prognóstico , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/química , Receptor ErbB-2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Indian J Pathol Microbiol ; 63(1): 86-89, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32031129

RESUMO

Increasing HER-2/neu resistance in gastric carcinoma has encouraged search for new biomarkers for targeted therapy. Cellular mesenchymal epithelial transition (C-MET) is one such tyrosine kinase inhibitor proposed for personalized salvage treatment. We determined frequency of C-MET gene copy number variation (CNV) by Fluorescent in-situ hybridization (FISH) in gastric adenocarcinoma (GAC) and sought its correlation with conventional clinicopathologic parameters. Dual-coloured FISH was done on 32 GAC cases. C-MET gene and centromere 7 signals were counted under fluorescent microscope and ratio was calculated for each case. Correlation between C-MET CNV and conventional clinic-pathologic parameters was done by Fischer exact test. CNV was identified in the form of amplification and polysomy (3.1% each) and associated with poorer prognostic parameters. Our pilot study highlights limited subset of patients that may benefit from anti-C-MET-targeted therapy and thus could be a novel biomarker for targeted intervention in GAC.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/terapia , Dosagem de Genes , Proteínas Proto-Oncogênicas c-met/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Receptor ErbB-2/genética , Adulto Jovem
16.
Toxicol Appl Pharmacol ; 392: 114918, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32045588

RESUMO

Orlistat (Xenical™), a US Food and Drug Administration (FDA)-approved anti-obesity drug, shows efficacy against multiple tumor types, including hepatocellular carcinoma (HCC), due to its ability to inhibit fatty acid synthase (FASN) activity. However, whether orlistat affects hepatocellular malignant transformation during hepatocarcinogenesis in vivo is unknown. This study assessed the antisteatotic and antitumorigenic efficacy of orlistat in a rapid HCC FVB/N mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes. Human hepatoma cell lines were used for mechanical validation in vitro. Hematoxylin and eosin staining, immunohistochemistry, and immunoblotting were applied for the mechanistic investigation. The results revealed that when orlistat was administered in the early stage of AKT/c-Met-triggered hepatocarcinogenesis, it resulted in the elimination of hepatic tumor burden. Mechanistically, orlistat efficiently elevated PTEN expression and suppressed AKT/SREBP1/FASN signaling both in vivo and in vitro, impairing AKT/c-Met-driven de novo lipogenesis and aberrant proliferation. Altogether, this study demonstrates the antilipogenic and antiproliferative efficacy of orlistat in hepatocarcinogenesis, suggesting that orlistat may be beneficial for the treatment of HCC, especially in NAFLD-related HCCs featuring activated AKT/mTOR cascade and increased lipogenesis in livers.


Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Fígado/metabolismo , Orlistate/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/farmacologia
17.
Lancet Oncol ; 21(3): 373-386, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32027846

RESUMO

BACKGROUND: Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study. METHODS: In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov, NCT02143466. FINDINGS: Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39-56) patients in part B and 23 (64%; 46-79) in part D. INTERPRETATION: The combination of osimertinib and savolitinib has acceptable risk-benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs. FUNDING: AstraZeneca.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Amplificação de Genes , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/genética , Acrilamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Método Duplo-Cego , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/administração & dosagem , Terapia de Salvação , Taxa de Sobrevida , Triazinas/administração & dosagem
18.
Sci Rep ; 10(1): 453, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949213

RESUMO

Mature microRNAs are short non-coding RNA sequences which upon incorporation into the RISC ribonucleoprotein complex, play a crucial role in regulation of gene expression. However, miRNAs can exist within the cell also as free molecules fulfilling their biological activity. Therefore, it is emerging that in addition to sequence even the structure adopted by mature miRNAs might play an important role to reach the target. Indeed, we analysed by several spectroscopic techniques the secondary structures of two artificial miRNAs selected by computational tool (miR-Synth) as best candidates to silence c-MET and EGFR genes and of two endogenous miRNAs (miR-15a and miR-15b) having the same seed region, but different biological activity. Our results demonstrate that both endogenous and artificial miRNAs can arrange in several 3D-structures which affect their activity and selectivity toward the targets.


Assuntos
MicroRNAs/química , MicroRNAs/genética , Sequência de Bases , Receptores ErbB/deficiência , Receptores ErbB/genética , Inativação Gênica , Conformação de Ácido Nucleico , Proteínas Proto-Oncogênicas c-met/deficiência , Proteínas Proto-Oncogênicas c-met/genética , Análise de Sequência de RNA
20.
Nat Med ; 26(1): 47-51, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31932802

RESUMO

MET exon 14 alterations are oncogenic drivers of non-small-cell lung cancers (NSCLCs)1. These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition2. Crizotinib is a multikinase inhibitor with potent activity against MET3. The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 21-45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.4-12.7). The median progression-free survival was 7.3 months (95% CI, 5.4-9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Crizotinibe/uso terapêutico , Éxons/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação/genética , Proteínas Proto-Oncogênicas c-met/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/farmacologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade
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