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1.
Anticancer Res ; 40(10): 5593-5600, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988883

RESUMO

BACKGROUND: Despite improved treatment for gastric cancer (GC), the prognosis of advanced disease remains poor. Further investigation of the oncogenic sequence for GC is needed. MATERIALS AND METHODS: The expression of TYRO3 protein tyrosine kinase in five GC cell lines was confirmed using western blotting. TYRO3 knockdown in GC cells, and bromodeoxyuridine and Transwell assays were used to examine the functions of TYRO3 in tumor proliferation and invasion. Finally, TYRO3 expression in 138 patients who underwent curative gastric resection for advanced GC (Union for International Cancer Control stage II/III) was tested by immunohistochemistry, and the association between prognosis and TYRO3 expression was analyzed. RESULTS: TYRO3 was detected at various levels in all the tested GC cell lines. Deleting TYRO3 significantly suppressed proliferation and invasion. Immunohistochemistry revealed TYRO3 expression was an independent prognostic factor for overall survival in patients with GC. CONCLUSION: TYRO3 appears to mediate tumor progression and predict prognosis of patients with GC.


Assuntos
Biomarcadores Tumorais/genética , Prognóstico , Receptores Proteína Tirosina Quinases/genética , Neoplasias Gástricas/genética , Idoso , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia
2.
Yonsei Med J ; 61(7): 562-571, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32608199

RESUMO

Melanoma, originating from epidermal melanocytes, is a heterogeneous disease that has the highest mortality rate among all types of skin cancers. Numerous studies have revealed the cause of this cancer as related to various somatic driver mutations, including alterations in KIT-a proto-oncogene encoding for a transmembrane receptor tyrosine kinase. Although accounting for only 3% of all melanomas, mutations in c-KIT are mostly derived from acral, mucosal, and chronically sun-damaged melanomas. As an important factor for cell differentiation, proliferation, and survival, inhibition of c-KIT has been exploited for clinical trials in advanced melanoma. Here, apart from the molecular background of c-KIT and its cellular functions, we will review the wide distribution of alterations in KIT with a catalogue of more than 40 mutations reported in various articles and case studies. Additionally, we will summarize the association of KIT mutations with clinicopathologic features (age, sex, melanoma subtypes, anatomic location, etc.), and the differences of mutation rate among subgroups. Finally, several therapeutic trials of c-KIT inhibitors, including imatinib, dasatinib, nilotinib, and sunitinib, will be analyzed for their success rates and limitations in advanced melanoma treatment. These not only emphasize c-KIT as an attractive target for personalized melanoma therapy but also propose the requirement for additional investigational studies to develop novel therapeutic trials co-targeting c-KIT and other cytokines such as members of signaling pathways and immune systems.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Proteínas Proto-Oncogênicas c-kit/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Feminino , Humanos , Masculino , Melanoma/genética , Membrana Mucosa/metabolismo , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores Proteína Tirosina Quinases/genética , Neoplasias Cutâneas/genética
3.
Nat Commun ; 11(1): 3586, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681075

RESUMO

Aberrant expression of receptor tyrosine kinase AXL is linked to metastasis. AXL can be activated by its ligand GAS6 or by other kinases, but the signaling pathways conferring its metastatic activity are unknown. Here, we define the AXL-regulated phosphoproteome in breast cancer cells. We reveal that AXL stimulates the phosphorylation of a network of focal adhesion (FA) proteins, culminating in faster FA disassembly. Mechanistically, AXL phosphorylates NEDD9, leading to its binding to CRKII which in turn associates with and orchestrates the phosphorylation of the pseudo-kinase PEAK1. We find that PEAK1 is in complex with the tyrosine kinase CSK to mediate the phosphorylation of PAXILLIN. Uncoupling of PEAK1 from AXL signaling decreases metastasis in vivo, but not tumor growth. Our results uncover a contribution of AXL signaling to FA dynamics, reveal a long sought-after mechanism underlying AXL metastatic activity, and identify PEAK1 as a therapeutic target in AXL positive tumors.


Assuntos
Movimento Celular , Adesões Focais/metabolismo , Neoplasias/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Adesões Focais/genética , Humanos , Invasividade Neoplásica , Neoplasias/genética , Neoplasias/fisiopatologia , Paxilina/genética , Paxilina/metabolismo , Fosforilação , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais
4.
Mol Cell ; 79(3): 390-405.e7, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32619402

RESUMO

Despite their apparent lack of catalytic activity, pseudokinases are essential signaling molecules. Here, we describe the structural and dynamic properties of pseudokinase domains from the Wnt-binding receptor tyrosine kinases (PTK7, ROR1, ROR2, and RYK), which play important roles in development. We determined structures of all pseudokinase domains in this family and found that they share a conserved inactive conformation in their activation loop that resembles the autoinhibited insulin receptor kinase (IRK). They also have inaccessible ATP-binding pockets, occluded by aromatic residues that mimic a cofactor-bound state. Structural comparisons revealed significant domain plasticity and alternative interactions that substitute for absent conserved motifs. The pseudokinases also showed dynamic properties that were strikingly similar to those of IRK. Despite the inaccessible ATP site, screening identified ATP-competitive type-II inhibitors for ROR1. Our results set the stage for an emerging therapeutic modality of "conformational disruptors" to inhibit or modulate non-catalytic functions of pseudokinases deregulated in disease.


Assuntos
Moléculas de Adesão Celular/química , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/química , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/química , Sequência de Aminoácidos , Animais , Baculoviridae/genética , Baculoviridae/metabolismo , Sítios de Ligação , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Clonagem Molecular , Cristalografia por Raios X , Expressão Gênica , Humanos , Camundongos , Modelos Moleculares , Células Precursoras de Linfócitos B/citologia , Células Precursoras de Linfócitos B/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/antagonistas & inibidores , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Receptores da Família Eph/antagonistas & inibidores , Receptores da Família Eph/química , Receptores da Família Eph/genética , Receptores da Família Eph/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Células Sf9 , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Spodoptera , Homologia Estrutural de Proteína , Especificidade por Substrato
5.
Anticancer Res ; 40(6): 3485-3489, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487648

RESUMO

BACKGROUND/AIM: Despite early detection by widespread use of abdominal imaging more than 40% of patients with conventional renal cell carcinoma (RCC) will die due to metastatic disease. Small kinase inhibitors for AXL receptor tyrosine kinase may delay the progression of metastatic cRCC. PATIENTS AND METHODS: We analysed AXL expression by immunohistochemistry on tissue multi arrays of 691 conventional RCC without metastasis at the time of nephrectomy. RESULTS: The Kaplan-Meier survival analysis indicated a poor disease-specific survival rates for patients with tumour showing cytoplasmic AXL staining, whereas expression on the cell membrane is associated with excellent disease outcome. Multivariate Cox regression analysis identified cytoplasmic AXL expression as an independent prognostic factor indicating a five-times higher risk of postoperative tumour progression (RR=5.048; 95% CI=2.391-10.657; p<0.001). CONCLUSION: Detecting cytoplasmic expression of AXL can be used to define a subset of conventional RCC with high risk of progression, thus identifying patients for more aggressive surveillance and adjuvant AXL inhibitor treatment as early as possible.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/cirurgia , Citoplasma/metabolismo , Progressão da Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Recidiva , Resultado do Tratamento , Adulto Jovem
6.
Adv Cancer Res ; 147: 1-57, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32593398

RESUMO

Growth factors and their receptor tyrosine kinases (RTKs), a group of transmembrane molecules harboring cytoplasm-facing tyrosine-specific kinase functions, play essential roles in migration of multipotent cell populations and rapid proliferation of stem cells' descendants, transit amplifying cells, during embryogenesis and tissue repair. These intrinsic functions are aberrantly harnessed when cancer cells undergo intertwined phases of cell migration and proliferation during cancer progression. For example, by means of clonal expansion growth factors fixate the rarely occurring driver mutations, which initiate tumors. Likewise, autocrine and stromal growth factors propel angiogenesis and penetration into the newly sprouted vessels, which enable seeding micro-metastases at distant organs. We review genetic and other mechanisms that preempt ligand-mediated activation of RTKs, thereby supporting sustained cancer progression. The widespread occurrence of aberrant RTKs and downstream signaling pathways in cancer, identifies molecular targets suitable for pharmacological intervention. We list all clinically approved cancer drugs that specifically intercept oncogenic RTKs. These are mainly tyrosine kinase inhibitors and monoclonal antibodies, which can inhibit cancer but inevitably become progressively less effective due to adaptive rewiring processes or emergence of new mutations, processes we overview. Similarly important are patient treatments making use of radiation, chemotherapeutic agents and immune checkpoint inhibitors. The many interfaces linking RTK-targeted therapies and these systemic or local regimens are described in details because of the great promise offered by combining pharmacological modalities.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Progressão da Doença , Humanos , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias/genética , Neoplasias/patologia , Inibidores de Proteínas Quinases/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais
8.
PLoS Genet ; 16(5): e1008767, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32357156

RESUMO

Despite the importance of dendritic targeting in neural circuit assembly, the mechanisms by which it is controlled still remain incompletely understood. We previously showed that in the developing Drosophila antennal lobe, the Wnt5 protein forms a gradient that directs the ~45˚ rotation of a cluster of projection neuron (PN) dendrites, including the adjacent DA1 and VA1d dendrites. We report here that the Van Gogh (Vang) transmembrane planar cell polarity (PCP) protein is required for the rotation of the DA1/VA1d dendritic pair. Cell type-specific rescue and mosaic analyses showed that Vang functions in the olfactory receptor neurons (ORNs), suggesting a codependence of ORN axonal and PN dendritic targeting. Loss of Vang suppressed the repulsion of the VA1d dendrites by Wnt5, indicating that Wnt5 signals through Vang to direct the rotation of the DA1 and VA1d glomeruli. We observed that the Derailed (Drl)/Ryk atypical receptor tyrosine kinase is also required for the rotation of the DA1/VA1d dendritic pair. Antibody staining showed that Drl/Ryk is much more highly expressed by the DA1 dendrites than the adjacent VA1d dendrites. Mosaic and epistatic analyses showed that Drl/Ryk specifically functions in the DA1 dendrites in which it antagonizes the Wnt5-Vang repulsion and mediates the migration of the DA1 glomerulus towards Wnt5. Thus, the nascent DA1 and VA1d glomeruli appear to exhibit Drl/Ryk-dependent biphasic responses to Wnt5. Our work shows that the final patterning of the fly olfactory map is the result of an interplay between ORN axons and PN dendrites, wherein converging pre- and postsynaptic processes contribute key Wnt5 signaling components, allowing Wnt5 to orient the rotation of nascent synapses through a PCP mechanism.


Assuntos
Antenas de Artrópodes/crescimento & desenvolvimento , Dendritos/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/crescimento & desenvolvimento , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Wnt/metabolismo , Animais , Antenas de Artrópodes/metabolismo , Axônios/metabolismo , Padronização Corporal , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Membrana/genética , Neurônios Receptores Olfatórios/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais , Proteínas Wnt/genética
9.
Science ; 368(6492): 731-736, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32409469

RESUMO

The establishment of reproductive barriers between populations can fuel the evolution of new species. A genetic framework for this process posits that "incompatible" interactions between genes can evolve that result in reduced survival or reproduction in hybrids. However, progress has been slow in identifying individual genes that underlie hybrid incompatibilities. We used a combination of approaches to map the genes that drive the development of an incompatibility that causes melanoma in swordtail fish hybrids. One of the genes involved in this incompatibility also causes melanoma in hybrids between distantly related species. Moreover, this melanoma reduces survival in the wild, likely because of progressive degradation of the fin. This work identifies genes underlying a vertebrate hybrid incompatibility and provides a glimpse into the action of these genes in natural hybrid populations.


Assuntos
Ciprinodontiformes/genética , Doenças dos Peixes/genética , Proteínas de Peixes/genética , Hibridização Genética , Melanoma/genética , Melanoma/virologia , Receptores Proteína Tirosina Quinases/genética , Alelos , Nadadeiras de Animais/patologia , Animais , Quimera , Loci Gênicos , Estudo de Associação Genômica Ampla
10.
Proc Natl Acad Sci U S A ; 117(17): 9365-9376, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32284408

RESUMO

The electrically silent (KvS) members of the voltage-gated potassium (Kv) subfamilies Kv5, Kv6, Kv8, and Kv9 selectively modulate Kv2 subunits by forming heterotetrameric Kv2/KvS channels. Based on the reported 3:1 stoichiometry of Kv2.1/Kv9.3 channels, we tested the hypothesis that Kv2.1/Kv6.4 channels express, in contrast to the assumed 3:1, in a 2:2 stoichiometry. We investigate the Kv2.1/Kv6.4 stoichiometry using single subunit counting and functional characterization of tetrameric concatemers. For selecting the most probable stoichiometry, we introduce a model-selection method that is applicable for any multimeric complex by investigating the stoichiometry of Kv2.1/Kv6.4 channels. Weighted likelihood calculations bring rigor to a powerful technique. Using the weighted-likelihood model-selection method and analysis of electrophysiological data, we show that Kv2.1/Kv6.4 channels express, in contrast to the assumed 3:1, in a 2:2 stoichiometry. Within this stoichiometry, the Kv6.4 subunits have to be positioned alternating with Kv2.1 to express functional channels. The variability in Kv2/KvS assembly increases the diversity of heterotetrameric configurations and extends the regulatory possibilities of KvS by allowing the presence of more than one silent subunit.


Assuntos
Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Potássio/metabolismo , Canais de Potássio Shab/metabolismo , Animais , Anticorpos , Linhagem Celular , Fibroblastos , Regulação da Expressão Gênica , Células HEK293 , Humanos , Potenciais da Membrana , Camundongos , Oócitos/metabolismo , Fotodegradação , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Receptores Proteína Tirosina Quinases/genética , Proteínas Recombinantes , Canais de Potássio Shab/genética , Canais de Potássio Shab/imunologia , Xenopus
11.
Semin Oncol ; 47(1): 73-84, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32201016

RESUMO

Soft-tissue sarcomas (STS) are a group of rare mesenchymal tumors that constitutes ∼1% of all solid tumors. It remains a rare tumor which lacks effective treatment options. Precision oncology may be of interest in this regard by identifying potential targets for emerging novel therapies. Neurotrophic receptor tyrosine kinase (NTRK) fusions are rare oncogenic driver mutations found in a broad range of common and rare tumor subtypes including STS. The recent approvals of NTRK inhibitors (larotrectinib and entrectinib) represent new therapeutic options in the drug armamentarium especially valuable in advanced STS given the paucity of treatment options and the generally poor prognosis of these tumors. We review the methods used to detect NTRK fusions in STS with focus on incidence, diagnosis and management of these rare and intriguing oncogenic targets.


Assuntos
Biomarcadores Tumorais , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sarcoma/tratamento farmacológico , Sarcoma/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Testes Genéticos , Humanos , Terapia de Alvo Molecular , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Sarcoma/diagnóstico , Sarcoma/epidemiologia , Resultado do Tratamento
12.
J Pathol ; 251(1): 74-86, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32162306

RESUMO

Serrated polyps are a clinically and molecularly heterogeneous group of lesions that can contribute to the development of colorectal cancers (CRCs). However, the molecular mechanism underlying the development of serrated lesions is still not well understood. Here, we combined multiple approaches to analyze the genetic alterations in 86 colorectal adenomas (including 35 sessile serrated lesions, 15 traditional adenomas, and 36 conventional adenomatous polyps). We also investigated the in vitro and in vivo oncogenic properties of a novel variant of the NCOA4-RET fusion gene. Molecular profiling revealed that sessile serrated lesions and traditional serrated adenomas have distinct clinicopathological and molecular features. Moreover, we identified receptor tyrosine kinase translocations exclusively in sessile serrated lesions (17%), and the observation was validated in a separate cohort of 34 sessile serrated lesions (15%). The kinase fusions as well as the BRAF and KRAS mutations were mutually exclusive to each other. Ectopic expression of a novel variant of the NCOA4-RET fusion gene promoted cell proliferation in vitro and in vivo, and the proliferation was significantly suppressed by RET kinase inhibitors. All of these underscored the importance of mitogen-activated protein kinase (MAPK) pathway activation in the serrated pathway of colorectal tumorigenesis. In addition, we demonstrated that the kinase fusion may occur early in the precursor lesion and subsequent loss of TP53 may drives the transformation to carcinoma during serrated tumorigenesis. In conclusion, we identified kinase fusions as a significant alternative driver of the serrated pathway in colorectal cancer development, and detecting their presence may serve as a biomarker for the diagnosis of sessile serrated lesions. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Neoplasias do Colo/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores Proteína Tirosina Quinases/genética , Adenoma/genética , Adenoma/patologia , Animais , Neoplasias do Colo/genética , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Camundongos , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas ras/genética , Proteínas ras/metabolismo
13.
Bull Cancer ; 107(4): 499-505, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32063345

RESUMO

Gastrointestinal stromal tumors (GIST) are the most common non-epithelial tumors of the gastrointestinal tract. Wild-type GISTs (WT-GIST) consist of a rare heterogeneous group characterized by the lack of activating mutations in the tyrosine kinase receptor (Kit) and/or platelet derived growth factor receptor A (PDGFRA). However, WT-GIST is characterized by other genomic alterations, including dehydrogenase succinate (SDH) deficiency or mutations in the Ras pathway. Recent studies have reported many mutations in others genes that may be incriminated in the development of WT-GISTs. Moreover, WT-GIST is frequently associated with hereditary cancer syndromes such as the Carney Triad and Type 1 Neurofibromatosis (NF1). WT-GIST affects usually young and pediatric patients. Most WT-GIST subtypes are insensitive to imatinib; therefore, their therapeutic management is somewhat different from usual GISTs. This review resumes the molecular and therapeutic features of this rare entity.


Assuntos
Tumores do Estroma Gastrointestinal/genética , Condroma/genética , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/terapia , Genes ras , Humanos , Leiomiossarcoma/genética , Neoplasias Pulmonares/genética , Mutação , Neurofibromatose 1/genética , Paraganglioma Extrassuprarrenal/genética , Doenças Raras , Receptores Proteína Tirosina Quinases/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Neoplasias Gástricas/genética , Succinato Desidrogenase/deficiência
14.
Medicine (Baltimore) ; 99(3): e18726, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011450

RESUMO

Immune-checkpoint inhibitor (ICI) efficacy in patients with non-small cell lung cancer (NSCLC) harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against epidermal growth-factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1)-mutated NSCLC patients in the real-world setting.In this retrospective, multicenter study on adults with ICI-treated EGFR-mutated or ALK- or ROS1-translated NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, and progression-free survival (PFS), objective response rate, duration of response, and overall survival (OS) from immunotherapy initiation.Fifty-one NSCLC patients (mean age, 58.0 years) were included from 20 French centers: 61% were never-smokers and 59% were women. Among them, 82% had EGFR-activating mutations, 16% ALK translocations, or 2% ROS1 translocations. Before ICI therapy, patients had received a median of 3 treatment lines (including tyrosine-kinase inhibitor). The median PFS was 2.1 (95% confidence interval [CI], 1.5-3.2) months for the entire cohort, 2.2 (95% CI, 1.4-3.2) for EGFR-mutated patients, and 2.4 (95% CI, 2.1-not reached) months for ALK-translocated patients. The median OS was 14.7 (95% CI, 12.1-19.2) months for the entire population and 13.9 (95% CI, 8.8-20.0) and 19.2 (95% CI, 13.1-not reached) months for EGFR-mutated and ALK-translocated patients, respectively. Seven (13.7%) patients were treated with ICI for >9 months. Toxicities were reported in 22% (11/51), including 8% (4/51) grade ≥3.In this real-world setting, analysis of ICI PFS against EGFR-mutated or ALK-translocated NSCLC patients appeared close to that observed in pretreated unselected NSCLC patients. The more promising OS probably linked to post-ICI treatments. Large prospective studies on these patient subsets are needed.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Quinase do Linfoma Anaplásico/genética , Receptores ErbB/genética , Feminino , França , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Receptores Proteína Tirosina Quinases/genética , Estudos Retrospectivos , Translocação Genética
15.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(2): 120-125, 2020 Feb 12.
Artigo em Chinês | MEDLINE | ID: mdl-32062881

RESUMO

Objective: To study the prevalence of c-ros oncogene 1 fusion in lung adenocarcinoma and to evaluate its relationship with clinical characteristics. Methods: We retrospectively analyzed epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) fusion in 1 482 patients with adenocarcinoma from March 2014 to January 2017 in the first affiliated hospital of Zhejiang University. Furthermore, ROS1 fusion positive patients diagnosed between February 2017 and December 2017 were also included in ROS1 positive group. The data of age, sex, smoking history, TNM stage and chest computed tomography were collected by Electronic Medical Record (EMR). The clinical data were compared by the chi-squared test or Mann-Whitney test. Results: Of these 1 482 patients,54 cases were diagnosed with ROS1 rearrangement, including 19 males and 35 females, while 73 cases were diagnosed with ALK rearrangement, including 28 males and 45 females, and 679 cases diagnosed with EGFR mutation including 293 males and 386 females. And there were 676 patients without driven genes mutation. The mean age in ROS1 fusion group (54±12) was lower than EGFR mutation group (60±11, z=-3.982, P<0.001) and WT group (62±10, z=-4.944, P<0.001). Female proportion in ROS1 fusion group (64.8%, 35/54) was higher than WT group (28.4%, 192/676, χ(2)=30.94, P<0.001). Non-smoker percentages in ROS1 fusion group (72.2%, 39/54) was significantly higher than WT group (38.0%,257/676, χ(2)=24.27, P<0.001). ROS1 fusion group was similar to ALK fusion group in sex, age and smoking history, and there were no significant difference in TNM stage among these groups. On chest CT, adenocarcinomas with ROS1 fusion were found to be more peripheral in location (71.4%, 20/28) and solid in density (75%, 21/28), usually with lobulated margins (75.0%, 21/28) and spiculated in contour (57.1%,16/28). Conclusion: In our study lung adenocarcinoma with c-ROS oncogene 1 fusion was a rare subtype lung cancer and was usually detected in young, never smoking, and female patients.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Quinase do Linfoma Anaplásico/genética , Receptores ErbB/genética , Neoplasias Pulmonares/diagnóstico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Adenocarcinoma de Pulmão/epidemiologia , Adenocarcinoma de Pulmão/genética , Adulto , Idoso , Quinase do Linfoma Anaplásico/metabolismo , China/epidemiologia , Feminino , Fusão Gênica/genética , Genes erbB-1 , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas de Fusão Oncogênica , Prevalência , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio , Estudos Retrospectivos
16.
J Pathol ; 250(5): 532-540, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32073140

RESUMO

Capicua, encoded by the gene CIC, is an evolutionarily conserved high-mobility group-box transcription factor downstream of the receptor tyrosine kinase and mitogen-activated protein kinase pathways. It was initially discovered and studied in Drosophila. Recurrent mutations in CIC were first identified in oligodendroglioma, a subtype of low-grade glioma. Subsequent studies have identified CIC aberrations in multiple types of cancer and have established CIC as a potent tumour suppressor involved in regulating pathways related to cell growth and proliferation, invasion and treatment resistance. The most well-known and studied targets of mammalian CIC are the oncogenic E-Twenty Six transcription factors ETV1/4/5, which have been found to be elevated in cancers with CIC aberrations. Here, we review the role of CIC in normal mammalian development, oncogenesis and tumour progression, and the functional interactors that mediate them. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Genes Supressores de Tumor/fisiologia , Receptores Proteína Tirosina Quinases/genética , Proteínas Repressoras/genética , Animais , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Fatores de Transcrição/metabolismo
17.
Dis Markers ; 2020: 1614627, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32051695

RESUMO

Rheumatoid Arthritis (RA) is the most common chronic inflammatory autoimmune disease involving joints. Among several pathogenic mechanisms, the impairment of homeostatic regulators of inflammation seems to be critically important to sustain persistent infiltration and activation of immune and stromal cells within the diseased synovium. Tyrosine kinase receptors Tyro3, Axl, and Mer are members of the TAM family. Upon binding their ligands Growth Arrest-Specific gene 6 (Gas6) and Protein S (ProS1), TAM receptors (TAMs) exert numerous and diverse biologic functions. Activated Axl and Mer, for instance, can negatively regulate the inflammatory cascade and mediate phagocytosis of apoptotic cells, contributing to prevent the development of autoimmunity. Thus, a role for TAMs has been hypothesized in RA. In this review, we will summarise unmet clinical needs in RA, depict the biology of TAMs and TAM ligands, focussing on their ability to regulate the immune system and inflammation cascade, and finally offer an overview of the state-of-the-art literature about the putative role of TAM axis in RA.


Assuntos
Artrite Reumatoide/imunologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , c-Mer Tirosina Quinase/metabolismo , Imunidade Adaptativa , Artrite Reumatoide/genética , Biomarcadores/metabolismo , Epigênese Genética , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Ligantes , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , c-Mer Tirosina Quinase/genética
18.
Indian J Pathol Microbiol ; 63(1): 7-12, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32031115

RESUMO

Background: It is well established that chronic exposure to tobacco induces head and neck cancers but the exact etiopathogenesis is not known. Though studies have shown expression of TIMP1, EPS8 and AXL in cancers, their role in tobacco-induced cancers is not known. We aimed this study to evaluate the role of these molecules in oral and oropharyngeal squamous cell cancers (SCC). Materials and Methods: In this single institutional study, 31 patients of oral and oropharyngeal SCC with history of chewing tobacco were included. Smokers were excluded from the study. After informed consent biopsies were taken from affected and contralateral normal mucosa. Paraffin blocks were made and tissue microarray (TMA) were constructed using these blocks. Immunohistochemistry (IHC) for TIMP1, EPS8, AXL kinase was carried out on these tissue microarrays. The intensity of staining was scored from 0 to 3+, related to expression of each of the three molecules. Results: The expression of TIMP1, EPS8 and AXL kinase was significantly more in the cancerous mucosa versus non-cancerous mucosa (P = 0.000 in all three) in oral and oropharyngeal SCC exposed to chewing tobacco. Conclusion: Immunohistochemical expression of these molecular markers in oral and oropharyngeal SCC correlated with their molecular based studies. Significant IHC expression of TIMP1, EPS8 and AXL establishes their role in the pathogenesis of oral and oropharyngeal squamous cell carcinomas. Novel targeted therapies may be researched that can detect and target these molecules at an earlier stage of pathogenesis of these tumors.


Assuntos
Neoplasias Bucais/induzido quimicamente , Neoplasias Orofaríngeas/induzido quimicamente , Tabaco sem Fumaça/efeitos adversos , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Índia , Masculino , Pessoa de Meia-Idade , Boca/patologia , Neoplasias Bucais/patologia , Neoplasias Orofaríngeas/patologia , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Centros de Atenção Terciária , Análise Serial de Tecidos , Inibidor Tecidual de Metaloproteinase-1/genética
19.
PLoS Genet ; 16(1): e1008433, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961852

RESUMO

Plant cells are encased in a semi-rigid cell wall of complex build. As a consequence, cell wall remodeling is essential for the control of growth and development as well as the regulation of abiotic and biotic stress responses. Plant cells actively sense physico-chemical changes in the cell wall and initiate corresponding cellular responses. However, the underlying cell wall monitoring mechanisms remain poorly understood. In Arabidopsis the atypical receptor kinase STRUBBELIG (SUB) mediates tissue morphogenesis. Here, we show that SUB-mediated signal transduction also regulates the cellular response to a reduction in the biosynthesis of cellulose, a central carbohydrate component of the cell wall. SUB signaling affects early increase of intracellular reactive oxygen species, stress gene induction as well as ectopic lignin and callose accumulation upon exogenous application of the cellulose biosynthesis inhibitor isoxaben. Moreover, our data reveal that SUB signaling is required for maintaining cell size and shape of root epidermal cells and the recovery of root growth after transient exposure to isoxaben. SUB is also required for root growth arrest in mutants with defective cellulose biosynthesis. Genetic data further indicate that SUB controls the isoxaben-induced cell wall stress response independently from other known receptor kinase genes mediating this response, such as THESEUS1 or MIK2. We propose that SUB functions in a least two distinct biological processes: the control of tissue morphogenesis and the response to cell wall damage. Taken together, our results reveal a novel signal transduction pathway that contributes to the molecular framework underlying cell wall integrity signaling.


Assuntos
Proteínas de Arabidopsis/metabolismo , Celulose/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Arabidopsis , Proteínas de Arabidopsis/genética , Tamanho Celular , Parede Celular/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais , Estresse Fisiológico
20.
Int J Mol Sci ; 21(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906413

RESUMO

Muscle invasive bladder carcinoma is a highly malignant cancer with a high mortality rate, due to its tendency to metastasize. The tyrosine kinase recepteur d'origine nantais (RON) promotes bladder carcinoma metastasis. Lysophosphatidic acid (LPA) is a phospholipid derivative, which acts as a signaling molecule to activate three high affinity G-protein coupled receptors, LPA1, LPA2, and LPA3. This in turn leads to cell proliferation and contributes to oncogenesis. However, little is known about the effects of LPA on invasive bladder cancer (IBC). In this study, we discovered that LPA upregulated RON expression, which in turn promoted cell invasion in bladder cancer T24 cells. As expected, we found that the LPA receptor was essential for the LPA induced increase in RON expression. More interestingly, we discovered that LPA induced RON expression via the MAPK (ERK1/2, JNK1/2), Egr-1, AP-1, and NF-κB signaling axes. These results provide experimental evidence and novel insights regarding bladder malignancy metastasis, which could be helpful for developing new therapeutic strategies for IBC treatment.


Assuntos
Movimento Celular/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Neoplasias da Bexiga Urinária/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/antagonistas & inibidores , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Humanos , NF-kappa B/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/metabolismo , Neoplasias da Bexiga Urinária/metabolismo
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