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1.
Expert Rev Clin Pharmacol ; 12(10): 931-939, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31469968

RESUMO

Introduction: Detecting oncogenic drivers across multiple cancers has brought about a shift toward a more targeted therapeutic approach. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are genomic rearrangements containing the kinase domain of one of three tropomyosin receptor kinases (TRK) and a dimerization domain contributed by another gene, generating fusion proteins, which are oncogenic drivers, targetable with TRK inhibitors. Larotrectinib is a first-in-class TRK inhibitor, granted accelerated FDA approval for treating TRK fusion cancer. This breakthrough indication across cancer subtypes and ages, from infancy through adulthood, highlights the need to understand the heterogeneous patient population and cancer types studied in larotrectinib clinical trials. Areas covered: We provide a narrative review of preclinical, pharmacokinetic, efficacy, and safety data for larotrectinib from three clinical trials that led to regulatory approval. Expert opinion: Larotrectinib elicits impressive responses in most patients with TRK fusion cancer, regardless of tumor type and age. Treatment is well tolerated with a low rate of treatment-emergent grade 3-4 adverse events, dose reductions and discontinuations due to adverse events, and recent findings indicate patient-reported improvement in quality of life. This highlights the importance of early testing for NTRK gene fusions in cancers that may harbor them, even if rare.


Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Fusão Gênica , Humanos , Neoplasias/genética , Neoplasias/patologia , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Qualidade de Vida , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética
2.
Nat Cell Biol ; 21(6): 710-720, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160709

RESUMO

The capacity of stem cells to self-renew or differentiate has been attributed to distinct metabolic states. A genetic screen targeting regulators of mitochondrial dynamics revealed that mitochondrial fusion is required for the maintenance of male germline stem cells (GSCs) in Drosophila melanogaster. Depletion of Mitofusin (dMfn) or Opa1 led to dysfunctional mitochondria, activation of Target of rapamycin (TOR) and a marked accumulation of lipid droplets. Enhancement of lipid utilization by the mitochondria attenuated TOR activation and rescued the loss of GSCs that was caused by inhibition of mitochondrial fusion. Moreover, constitutive activation of the TOR-pathway target and lipogenesis factor Sterol regulatory element binding protein (SREBP) also resulted in GSC loss, whereas inhibition of SREBP rescued GSC loss triggered by depletion of dMfn. Our findings highlight a critical role for mitochondrial fusion and lipid homeostasis in GSC maintenance, providing insight into the potential impact of mitochondrial and metabolic diseases on the function of stem and/or germ cells.


Assuntos
Proteínas de Drosophila/genética , Proteínas de Membrana/genética , Dinâmica Mitocondrial/genética , Células-Tronco/metabolismo , Proteínas de Ligação a Elemento Regulador de Esterol/genética , Animais , Diferenciação Celular/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Homeostase , Metabolismo dos Lipídeos/genética , Masculino , Mitocôndrias/genética , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais/genética , Nicho de Células-Tronco/genética , Células-Tronco/citologia , Testículo/crescimento & desenvolvimento , Testículo/metabolismo
3.
Curr Top Med Chem ; 19(15): 1338-1349, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218961

RESUMO

Axl, a Receptor Tyrosine Kinase (RTK) belonging to the TAM (Axl, Mer, Tyro3) family, participates in many signal transduction cascades after mostly being stimulated by Growth arrestspecific 6(Gas6). Axl is widely expressed in many organs, such as macrophages, endothelial cells, heart, liver and skeletal muscle. Over-expression and activation of Axl are associated with promoting chemotherapy resistance, cell proliferation, invasion and metastasis in many human cancers, such as breast, lung, and pancreatic cancers. Therefore, the research and development of Axl inhibitors is of great significance to strengthen the means of cancer treatment, especially to solve the problem of drug resistance. Axl inhibitors have attracted more and more researchers' attention in recent years. This review discusses the research progress of Axl inhibitors in recent years.


Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade
4.
Nat Commun ; 10(1): 2701, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221965

RESUMO

One of the biggest hurdles for the development of metabolism-targeted therapies is to identify the responsive tumor subsets. However, the metabolic vulnerabilities for most human cancers remain unclear. Establishing the link between metabolic signatures and the oncogenic alterations of receptor tyrosine kinases (RTK), the most well-defined cancer genotypes, may precisely direct metabolic intervention to a broad patient population. By integrating metabolomics and transcriptomics, we herein show that oncogenic RTK activation causes distinct metabolic preference. Specifically, EGFR activation branches glycolysis to the serine synthesis for nucleotide biosynthesis and redox homeostasis, whereas FGFR activation recycles lactate to fuel oxidative phosphorylation for energy generation. Genetic alterations of EGFR and FGFR stratify the responsive tumors to pharmacological inhibitors that target serine synthesis and lactate fluxes, respectively. Together, this study provides the molecular link between cancer genotypes and metabolic dependency, providing basis for patient stratification in metabolism-targeted therapies.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Mutação com Ganho de Função , Perfilação da Expressão Gênica/métodos , Glicólise/efeitos dos fármacos , Glicólise/genética , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Metabolômica/métodos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Seleção de Pacientes , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Serina/biossíntese , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Nat Rev Dis Primers ; 5(1): 30, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048702

RESUMO

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or other AChR-related proteins in the postsynaptic muscle membrane. Localized or general muscle weakness is the predominant symptom and is induced by the antibodies. Patients are grouped according to the presence of antibodies, symptoms, age at onset and thymus pathology. Diagnosis is straightforward in most patients with typical symptoms and a positive antibody test, although a detailed clinical and neurophysiological examination is important in antibody-negative patients. MG therapy should be ambitious and aim for clinical remission or only mild symptoms with near-normal function and quality of life. Treatment should be based on MG subgroup and includes symptomatic treatment using acetylcholinesterase inhibitors, thymectomy and immunotherapy. Intravenous immunoglobulin and plasma exchange are fast-acting treatments used for disease exacerbations, and intensive care is necessary during exacerbations with respiratory failure. Comorbidity is frequent, particularly in elderly patients. Active physical training should be encouraged.


Assuntos
Miastenia Gravis/diagnóstico , Miastenia Gravis/terapia , Acetilcolinesterase/genética , Acetilcolinesterase/fisiologia , Corticosteroides/uso terapêutico , Agrina/genética , Agrina/fisiologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Autoanticorpos/análise , Autoanticorpos/sangue , Biomarcadores/análise , Biomarcadores/sangue , Blefaroptose/etiologia , Colágeno/genética , Colágeno/fisiologia , Cortactina/genética , Cortactina/fisiologia , Eletromiografia/métodos , Humanos , Canal de Potássio Kv1.4/genética , Canal de Potássio Kv1.4/fisiologia , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/fisiologia , Proteínas Musculares/genética , Proteínas Musculares/fisiologia , Miastenia Gravis/fisiopatologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/fisiologia , Receptores Colinérgicos/genética , Receptores Colinérgicos/fisiologia , Receptores Nicotínicos/genética , Fatores de Risco , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologia
6.
J Clin Pathol ; 72(7): 460-467, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31072837

RESUMO

The neurotrophic tyrosine receptor kinase (NTRK) gene family encodes three tropomyosin receptor kinases (TRKA, TRKB, TRKC) that contribute to central and peripheral nervous system development and function. NTRK gene fusions are oncogenic drivers of various adult and paediatric tumours. Several methods have been used to detect NTRK gene fusions including immunohistochemistry, fluorescence in situ hybridisation, reverse transcriptase polymerase chain reaction, and DNA- or RNA-based next-generation sequencing. For patients with TRK fusion cancer, TRK inhibition is an important therapeutic target. Following the FDA approval of the selective TRK inhibitor, larotrectinib, as well as the ongoing development of multi-kinase inhibitors with activity in TRK fusion cancer, testing for NTRK gene fusions should become part of the standard diagnostic process. In this review we discuss the biology of NTRK gene fusions, and we present a testing algorithm to aid detection of these gene fusions in clinical practice and guide treatment decisions.


Assuntos
Neoplasias/genética , Fatores de Crescimento Neural/genética , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Algoritmos , Humanos , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Fatores de Crescimento Neural/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor trkA/antagonistas & inibidores , Receptor trkA/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Receptor trkC/antagonistas & inibidores , Receptor trkC/genética
7.
Nat Commun ; 10(1): 1744, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988311

RESUMO

SCM, a leucine-rich repeat receptor-like kinase, is required for root epidermal cells to appropriately interpret their location and generate the proper cell-type pattern during Arabidopsis root development. Here, via a screen for scm-like mutants we describe a new allele of the QKY gene. We find that QKY is required for the appropriate spatial expression of several epidermal cell fate regulators in a similar manner as SCM in roots, and that QKY and SCM are necessary for the efficient movement of CPC between epidermal cells. We also show that turnover of SCM is mediated by a vacuolar degradation pathway triggered by ubiquitination, and that QKY prevents this SCM ubiquitination through their physical interaction. These results suggest that QKY stabilizes SCM through interaction, and this complex facilitates CPC movement between the epidermal cells to help establish the cell-type pattern in the Arabidopsis root epidermis.


Assuntos
Proteínas de Arabidopsis/fisiologia , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/citologia , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Morfogênese , Epiderme Vegetal/citologia , Epiderme Vegetal/metabolismo , Raízes de Plantas/citologia , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Proteínas Proto-Oncogênicas c-myb/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais
8.
Dis Markers ; 2019: 5380197, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944666

RESUMO

Cervical cancer is one of the most common malignant neoplasms in gynecology. Protein tyrosine kinase 7 (PTK7) with an inactive kinase domain is an important regulator of multiple Wnt pathways under normal and various pathological conditions and overexpressed in various tumors; however, the clinical and biological significance of PTK7 in cervical cancer is still unknown. In the present study, the protein expression level of PTK7 was detected in clinical cervical cancer patient samples, and the relationship between PTK7 expression and clinicopathological features was analyzed. In addition, the Kaplan-Meier method was performed to estimate the overall survival (OS) and progression-free survival (PFS) of patients to investigate the clinicopathological significance of PTK7 expression. Functional assays demonstrated that knocking down PTK7 might inhibit the ability of cancer cells to proliferate and invade or migrate, both in vivo and in vitro. Thus, PTK7 might serve as a potential target for cervical cancer.


Assuntos
Biomarcadores Tumorais/genética , Moléculas de Adesão Celular/genética , Receptores Proteína Tirosina Quinases/genética , Neoplasias do Colo do Útero/genética , Animais , Biomarcadores Tumorais/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Camundongos , Receptores Proteína Tirosina Quinases/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
9.
Int J Clin Oncol ; 24(7): 779-788, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30976939

RESUMO

BACKGROUND: In recent years, a better understanding of tumor biology and molecular features of gastric cancer has been reached. It may serve as a roadmap for patient stratification and trials of targeted therapies. The apparent efficacy of PD-1 blockade might be limited to a relatively small subset of advanced gastric cancer patients. MATERIALS AND METHODS: In this study, preclinical and clinical studies, which investigated molecular features, promising treatment targets, and immune checkpoint inhibitor in gastric cancer, were reviewed via PubMed and the congress webpages of the American Society of Clinical Oncology and European Society of Medical Oncology. RESULTS: Next-generation sequencing technologies have defined the genomic landscape of gastric cancer. Indeed, several molecular classifications have been proposed, and distinct molecular subtypes have been identified. Based on these molecular profiles, clinical trials of new agents such as receptor tyrosine kinases inhibitors, antibody-drug conjugates, and IMAB362 (anti-Claudin 18.2) are ongoing. In addition, biomarkers to predict response during immune checkpoint inhibitors and combination therapy have been enthusiastically investigated. CONCLUSION: Remarkable advances in an understanding of molecular profiles of gastric cancer enable the development of novel agents. The better treatment selection of immune checkpoint inhibitors or combination therapy should be established. These developments could facilitate precision medicine on gastric cancer in the near future.


Assuntos
Medicina de Precisão , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Terapia Combinada , Humanos , Terapia de Alvo Molecular , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Neoplasias Gástricas/classificação
10.
Nano Lett ; 19(4): 2603-2613, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30907088

RESUMO

Optogenetics provides promising tools for the precise control of receptor-mediated cell behaviors in a spatiotemporal manner. Yet, most photoreceptors require extensive genetic manipulation and respond only to ultraviolet or visible light, which are suboptimal for in vivo applications because they do not penetrate thick tissues. Here we report a novel near-infrared light-activated DNA agonist (NIR-DA) nanodevice for nongenetic manipulation of cell signaling and phenotype in deep tissues. This nanodevice is prepared by conjugating a preinactivated DNA agonist onto the gold nanorods (AuNRs). Upon NIR light treatment, the DNA agonist is released through the localized surface plasmon resonance (LSPR)-based photothermal effect of AuNRs and becomes active. The active DNA agonist dimerizes the DNA-modified chimeric or native receptor tyrosine kinase (RTK) on cell surfaces and activates downstream signal transduction in live cells. Such NIR-DA activation of RTK signaling enables the control of cytoskeletal remodeling, cell polarization, and directional migration. Furthermore, we demonstrate that the NIR-DA system can be used in vivo to mediate RTK signaling and skeletal muscle satellite cell migration and myogenesis, which are critical cellular behaviors in the process of skeletal muscle regeneration. Thus, the NIR-DA system offers a powerful and versatile platform for exogenous modulation of deep tissues for purposes such as regenerative medicine.


Assuntos
Materiais Biocompatíveis/farmacologia , Comunicação Celular/efeitos dos fármacos , DNA/genética , Receptores Proteína Tirosina Quinases/genética , Materiais Biocompatíveis/química , Comunicação Celular/efeitos da radiação , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/efeitos da radiação , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/efeitos da radiação , DNA/agonistas , DNA/química , DNA/efeitos dos fármacos , Ouro/química , Humanos , Raios Infravermelhos , Nanotubos/química , Receptores Proteína Tirosina Quinases/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Ressonância de Plasmônio de Superfície
11.
Mol Carcinog ; 58(6): 854-861, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30859654

RESUMO

Published evidence shows a correlation between several molecular markers and prostate cancer (PCa) progression including in African Americans (AAs) who are disproportionately affected. Our early detection efforts led to the identification of elevated levels of antiapoptotic protein, c-FLIP and its upstream regulatory factors such as androgen receptor (AR), recepteur d'origine nantais (RON), a receptor tyrosine kinase in human prostate tumors. The primary objective of this study was to explore whether these markers play a role in racial disparities using immunohistochemistry in prostatectomy samples from a cohort of AA, Hispanic Whites (HWs), and non-Hispanic Whites (NHWs). Bivariable and multivariable logistic regression analyses were used to identify a statistical association between molecular markers, possible correlation with risk factors including race, obesity, prostate-specific antigen (PSA) and disease aggressiveness. Further, changes in the levels and expression of these molecular markers were also evaluated using human PCa cell lines. We found significantly elevated levels of RON ( P = 0.0082), AR ( P = 0.0001), c-FLIP ( P = 0.0071) in AAs compared with HWs or NHWs. Furthermore, a higher proportion of HW and NHWs had a high Gleason score (>6) but not PSA as compared to AAs ( P = 0.032). In summary, our findings suggest that PSA was important in predicting aggressive disease for the cohort overall; however, high levels of RON may play a role in predisposing AA men to develop aggressive disease. Future research is needed using large datasets to confirm these findings and to explore whether all or any of these markers could aid in race-specific stratification of patients for treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/cirurgia , Receptores Proteína Tirosina Quinases/metabolismo , Regulação para Cima , Adulto , Afro-Americanos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Regulação Neoplásica da Expressão Gênica , Hispano-Americanos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prostatectomia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Androgênicos/metabolismo
12.
Mol Med Rep ; 19(4): 3230-3236, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816529

RESUMO

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR­TKI) is an excellent therapeutic agent to treat EGFR mutation­positive non­small cell lung cancer (NSCLC). However, the initial response decreases as chemoresistance develops. In the present study, gefitinib­resistant EGFR mutant NSCLC PC­9/GR cells were established to examine the characteristics and mechanisms associated with chemoresistance. Axl expression in PC­9/GR cells was transcriptionally upregulated, since Axl protein and mRNA expression levels were identified to be increased according to western blot analysis and reverse transcription polymerase chain reaction results. The inhibitory effect of celastrol on Axl protein expression level, cell viability and clonogenicity were identified in parental and gefitinib­resistant PC­9 cells. In addition, treatment of PC­9/GR cells with celastrol and gefitinib in combination was demonstrated to synergistically suppress Axl protein expression level, cell proliferation and migration. Taken together, upregulation of Axl expression seems to be associated with chemoresistance of PC­9/GR cells. Furthermore, celastrol targets Axl to exert its anticancer effects in order to increase the susceptibility of PC­9/GR cells to gefitinib and overcome chemoresistance.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Gefitinibe/farmacologia , Neoplasias Pulmonares/genética , Mutação , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Triterpenos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética
13.
J Exp Clin Cancer Res ; 38(1): 43, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30700325

RESUMO

BACKGROUND: Some membrane proteins can translocate into the nucleus, defined as nuclear localized membrane proteins (NLMPs), including receptor tyrosine kinases (RTKs). We previously showed that nuclear MET (nMET), a member of RTKs, mediates cancer stem-like cells self-renewal to promote cancer recurrence. However, it is unknown that nMET or mMET, which is the ancestor in the evolution of cancer cell survival and clearance. Here, we aim to study the NLMP functions in cell death, differentiation and survival. METHOD: We applied the systematic reanalysis of functional NLMP and clinical investigations of nMET from databases. In addition, we used soft agar assay, immunoblotting, flow cytometry, and immunofluorescence confocal microscopy for examinations of nMET functions including stem-like cell formation, cell signaling, cell cycle regulation, and co-localization with regulators of cell signaling. ShRNA, antibody of recognizing surface membrane MET based treatment were used to downregulate endogenous nMET to uncover its function. RESULTS: We predicted and demonstrated that nMET and nEGFR are most likely not ancestors. nMET overexpression induces both cell death and survival with drug resistance and stem cell-like characters. Moreover, the paradoxical function of nMET in both cell death and cell survival is explained by the fact that nMET induces stem cell-like cell growth, DNA damage repair, to evade the drug sensitization for survival of single cells while non-stem cell-like nMET expressing single cells may undergo clearance by cell death through cell cycle arrest induced by p21. CONCLUSION: Taken together, our data suggest a link between nuclear RTK and cancer cell evolutionary clearance via cell death, and drug resistance for survival through stemness selection. Targeting evolved nuclear RTKs in cancer stem cells would be a novel avenue for precision cancer therapy.


Assuntos
Núcleo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Apoptose , Núcleo Celular/genética , Proliferação de Células , Humanos , Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais , Células Tumorais Cultivadas
14.
Mol Cancer ; 18(1): 24, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744655

RESUMO

Axl receptor tyrosine kinase is involved in the growth and metastasis and is an indicator of poor prognosis in several cancers including lung cancers. Although a mitogen-activated protein kinase (MAPK) pathway and an epithelial-to-mesenchymal transition (EMT) program are critical, molecular mechanisms underlying the Axl-driven cancer progression have not been fully elucidated. We aimed to identify molecules up-regulated by Axl kinase in lung adenocarcinomas. Through the global gene expression analysis and the functional annotation clustering, we found that AXL expression positively correlated with mRNA expressions of immune checkpoint molecules and chemokine receptors in non-small-cell lung cancers. Validation cohorts including our biobank confirmed that the AXL expression significantly correlated with expression of genes encoding programmed death-ligand1 (PD-L1) and CXC chemokine receptor 6 (CXCR6) in lung adenocarcinoma, especially in epidermal growth factor receptor (EGFR) mutation-positive adenocarcinoma. Pharmacological inhibition of Axl kinase activity decreased mRNA expressions of PD-L1 and CXCR6 in EGFR mutation-positive cell lines. Our data indicates the novel role of Axl kinase as a driver of immune checkpoint molecules and chemokine signalling pathways in the progression of lung adenocarcinomas. This study also highlights the necessity of clinical trials in order to test the efficacy of Axl kinase inhibition in the Axl-highly expressing subset of lung adenocarcinomas. .


Assuntos
Adenocarcinoma de Pulmão/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Antineoplásicos/farmacologia , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Benzocicloeptenos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Estudos de Coortes , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/imunologia , Receptores ErbB/genética , Receptores ErbB/imunologia , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/imunologia , RNA Mensageiro/genética , RNA Mensageiro/imunologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Proteína Tirosina Quinases/imunologia , Receptores CXCR6/genética , Receptores CXCR6/imunologia , Transdução de Sinais/imunologia , Triazóis/farmacologia
15.
Pathol Int ; 69(2): 94-96, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30707464

RESUMO

Anti-TRK targeted therapies offer opportunities to treat patients with advanced NTRK1/2/3-rearranged cancers. Beyond NTRK-rearranged secretory breast carcinomas, little is known about NTRK rearrangements and the expression of TRK proteins in non-secretory breast carcinomas. We search for TRK proteins expressions using pan-TRK immunohistochemistry and NTRK1, NTRK2 and NTRK3 rearrangements using fluorescent in situ hybridization (FISH) tests in a set of tissue microarray included breast carcinomas. Only 1/339 invasive breast carcinomas, the only example of secretory subtype, was positive using pan-TRK immunohistochemistry and harboured a NTRK-rearrangement (NTRK1 positive FISH test). According to our results, druggable NTRK rearrangements and related-TRK proteins expression are not encountered in non-secretory breast carcinomas.


Assuntos
Neoplasias da Mama/genética , Carcinoma/genética , Receptores Proteína Tirosina Quinases/biossíntese , Receptores Proteína Tirosina Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma/metabolismo , Carcinoma/patologia , Feminino , Rearranjo Gênico , Humanos , Pessoa de Meia-Idade
16.
J Agric Food Chem ; 67(10): 2818-2830, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30789269

RESUMO

Ampelopsins A and C are resveratrol oligostilbenes whose role in cancer development remains unknown. This study evaluated the antimetastatic and apoptosis-inducing properties of ampelopsins A and C in MDA-MB-231 cells. The IC50 values of ampelopsins A and C against MDA-MB-231 cells at 72 h were 38.75 ± 4.61 and 2.71 ± 0.21 µM, respectively. However, at 24 h, ampelopsins A and C decreased cell metastasis significantly. Among the 71 proteins present on the human phosphoreceptor tyrosin kinase array, ampelopsin C decreased the phosphorylated protein level of AXL, Dtk (TYRO3), EphA2, EphA6, Fyn, Hck, and SRMS. Additionally, antiproliferation effects of ampelopsin C were enhanced when combined with luteolin and chrysin compared to either two or a single agent in MDA-MB-231 cells. Overall, ampelopsins A and C extracted from Vitis thunbergii are both novel antimetastatic agents and potential therapeutic targets in patients with breast cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Flavonoides/farmacologia , Proteínas Proto-Oncogênicas c-fyn/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Metástase Neoplásica , Fosforilação , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo
17.
Med Sci Monit ; 25: 1410-1422, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30793707

RESUMO

BACKGROUND Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a functional long non-coding RNA involved in many biologic processes. The study was aimed to explore the functional roles of MALAT1 in osteosarcoma progression. MATERIAL AND METHODS A total of 76 osteosarcoma tissues and paired adjacent non-tumor tissues were collected from surgical resection. MALAT1, miRNAs, and genes mRNA expression levels were detected using quantitative real-time PCR (qRT-PCR). Protein expression level, cell proliferation, migration, and invasion were assessed using western blot, Cell Counting Kit-8 (CCK-8), wound-healing assay, and Matrigel invasion assay respectively. The target relationships among miRNAs, MALAT1, and mRNA were detected via dual-luciferase reporter assay. RESULTS We found that MALAT1 was frequently upregulated in osteosarcoma samples and cell lines and a high level of MALAT1 predicted poor overall survival in osteosarcoma patients. Knockdown of MALAT1 inhibited proliferation, migration, and invasion of osteosarcoma cells. Further study showed a positive correlation between MALAT1 and c-Met or SOX4 expression. Mechanistic investigations demonstrated that MALAT1, as a competing endogenous RNA (ceRNA), regulated osteosarcoma proliferation and metastasis through competitively binding to miR-34a/c-5p and miR-449a/b. CONCLUSIONS Taken together, our study illustrates a new regulatory mechanism for MALAT1 and may provide a novel therapeutic strategy for the treatment of osteosarcoma.


Assuntos
Neoplasias Ósseas/metabolismo , MicroRNAs/metabolismo , Osteossarcoma/metabolismo , RNA Longo não Codificante/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Fatores de Transcrição SOXC/metabolismo , Adolescente , Adulto , Apoptose/fisiologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Criança , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Osteossarcoma/genética , Osteossarcoma/patologia , RNA Longo não Codificante/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores Proteína Tirosina Quinases/genética , Fatores de Transcrição SOXC/genética , Transdução de Sinais , Regulação para Cima
18.
Bull Exp Biol Med ; 166(3): 339-343, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30627913

RESUMO

We studied effects of semaphorin 3A, keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), and their combinations on the proliferative activity of cortical (cTEC1-2) and medullary (mTEC3-10) thymus epithelium cell lines. Semaphorin 3A inhibited the proliferative activity of epithelial cells, while HGF and KGF, in contrast, exerted a stimulating effect. The effect of KGF and semaphorin 3A on different cell lines depended on the expression of receptors for these two factors. When the combination of two factors was used, semaphorin 3A was able to neutralize the stimulating effect of HGF and KGF. It can be assumed that semaphorin 3A synthesized in the thymus stroma, can act as a functional antagonist of HGF and KGF and have an inhibitory effect when these drugs are administered into the body for the therapeutic purpose of restoring thymus functions.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Fator 7 de Crescimento de Fibroblastos/farmacologia , Fator de Crescimento de Hepatócito/farmacologia , RNA Mensageiro/genética , Semaforina-3A/farmacologia , Animais , Linhagem Celular , Combinação de Medicamentos , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Fator 7 de Crescimento de Fibroblastos/genética , Fator 7 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuropilina-1/genética , Neuropilina-1/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Semaforina-3A/genética , Semaforina-3A/metabolismo , Transdução de Sinais , Timo/citologia , Timo/metabolismo
19.
Future Oncol ; 15(6): 653-662, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30648886

RESUMO

The receptor tyrosine kinase Axl and its ligand Gas6 regulate fundamental biological processes, including cell proliferation, survival and motility, through multiple downstream signaling pathways. Evidence to date suggests that aberrant Axl expression frequently occurs in many malignancies, including hepatocellular carcinoma, and that this is critical for promoting cell proliferation, migration, angiogenesis and metastasis. Moreover, deregulated Axl expression or activation is reportedly associated with resistance to cancer drugs and targeted cancer therapies. Thus, Axl inhibitors may represent a novel therapeutic approach for cancer treatment. This Review summarizes the latest advances concerning the biological role of Axl in hepatocellular carcinoma and its potential clinical relevance.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Biomarcadores Tumorais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular , Prognóstico , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/genética , Relação Estrutura-Atividade
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