RESUMO
The genetic landscape of melanoma resistance to targeted therapy with small molecules inhibiting BRAF and MEK kinases is still largely undefined. In this study, we portrayed in detail the somatic alterations of resistant melanoma and explored the associated biological processes and their integration with transcriptional profiles. By targeted next-generation sequencing and whole-exome sequencing analyses, a list of 101 genes showing imbalance in metastatic tumors from patients with a complete/durable response or disease progression during therapy with vemurafenib or with dabrafenib and trametinib was defined. Classification of altered genes in functional categories indicated that the mutational pattern of both resistant tumors and melanoma cell lines was enriched in gene families involved in oncogenic signaling pathways and in DNA repair. Integration of genomic and transcriptomic features showed that the enrichment of mutations in gene sets associated with anabolic processes, chromatin alterations, and IFN-α response determined a significant positive modulation of the same gene signatures at the transcriptional level. In particular, MTORC1 signaling was enriched in tumors from poorly responsive patients and in resistant tumors excised from treated patients. Results indicate that genetic patterns are associated with melanoma resistance to targeted therapy and disclose the underlying key molecular pathways to define drug combinations for improved personalized therapies.
Assuntos
Melanoma , Proteínas Proto-Oncogênicas B-raf , Humanos , Vemurafenib/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/uso terapêutico , Mutação , Cromatina , Alvo Mecanístico do Complexo 1 de Rapamicina , Quinases de Proteína Quinase Ativadas por Mitógeno , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: Aberrant TAK1 (transforming growth factor ß-activated kinase 1) activity is known to be involved in a variety of malignancies, but the regulatory mechanisms of TAK1 remain poorly understood. GRAMD4 (glucosyltransferase Rab-like GTPase activator and myotubularin domain containing 4) is a newly discovered p53-independent proapoptotic protein with an unclear role in HCC (hepatocellular carcinoma). RESULTS: In this research, we found that GRAMD4 expression was lower in HCC samples, and its downregulation predicted worse prognosis for patients after surgical resection. Functionally, GRAMD4 inhibited HCC migration, invasion and metastasis. Mechanistically, GRAMD4 interacted with TAK1 to promote its protein degradation, thus, resulting in the inactivation of MAPK (Mitogen-activated protein kinase) and NF-κB pathways. Furthermore, GRAMD4 was proved to recruit ITCH (itchy E3 ubiquitin protein ligase) to promote the ubiquitination of TAK1. Moreover, high expression of TAK1 was correlated with low expression of GRAMD4 in HCC patients. CONCLUSIONS: GRAMD4 inhibits the migration and metastasis of HCC, mainly by recruiting ITCH to promote the degradation of TAK1, which leads to the inactivation of MAPK and NF-κB signalling pathways.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , MAP Quinase Quinase Quinases/antagonistas & inibidores , Proteínas Mitocondriais/farmacologia , Metástase Neoplásica/tratamento farmacológico , Carcinoma Hepatocelular/fisiopatologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/fisiopatologia , MAP Quinase Quinase Quinases/uso terapêutico , Proteínas Mitocondriais/uso terapêutico , Metástase Neoplásica/prevenção & controle , Proteínas Repressoras/farmacologia , Proteínas Repressoras/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ubiquitina-Proteína Ligases/farmacologia , Ubiquitina-Proteína Ligases/uso terapêuticoRESUMO
Intrauterine inflammation (IUI) associated with infection is the major cause of preterm birth (PTB) at <32 weeks' gestation and accounts for â¼40% of all spontaneous PTBs. Pharmacological strategies to prevent PTB and improve fetal outcomes will likely require both antimicrobial and anti-inflammatory therapies. Here we investigated the effects of two cytokine-suppressive anti-inflammatory drugs (CSAIDs), compounds that specifically target inflammatory signalling pathways, in an ovine model of lipopolysaccharide (LPS)-induced chorioamnionitis. Chronically catheterized ewes at 116 days gestation (n = 7/group) received an intra-amniotic (IA) bolus of LPS (10 mg) plus vehicle or CSAIDS: TPCA-1 (1.2 mg/kg fetal weight) or 5z-7-oxozeaenol (OxZnl; 0.4 mg/kg fetal weight); controls received vehicle (dimethylsulphoxide). Amniotic fluid (AF), fetal and maternal blood samples were taken 0, 2, 6, 12, 24 and 48 h later; tissues were taken at autopsy (48 h). Administration of TPCA-1 or OxZnl abrogated the stimulatory effects of LPS (P < 0.01 versus vehicle control) on production of PGE2 in AF, with lesser (non-significant) effects on IL-6 production. Fetal membrane polymorphonuclear cell infiltration score was significantly higher in LPS versus vehicle control animals (P < 0.01), and this difference was absent with TPCA-1 and OxZnl treatment. LPS-induced systemic fetal inflammation was highly variable, with no significant effects of CSAIDs observed. Lung inflammation was evident with LPS exposure, but unaffected by CSAID treatment. We have shown in a large animal model that IA administration of a single dose of CSAIDs can suppress LPS-induced IA inflammatory responses, while fetal effects were minimal. Further development and investigation of these compounds in infectious models is warranted.
Assuntos
Anti-Inflamatórios/uso terapêutico , Corioamnionite/prevenção & controle , Modelos Animais de Doenças , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tiofenos/uso terapêutico , Zearalenona/análogos & derivados , Líquido Amniótico/química , Animais , Anti-Inflamatórios/administração & dosagem , Biomarcadores/análise , Biomarcadores/sangue , Cateteres de Demora , Corioamnionite/imunologia , Corioamnionite/metabolismo , Corioamnionite/fisiopatologia , Feminino , Sangue Fetal/química , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/metabolismo , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , MAP Quinase Quinase Quinases/administração & dosagem , MAP Quinase Quinase Quinases/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Gravidez , Nascimento Prematuro/etiologia , Nascimento Prematuro/imunologia , Nascimento Prematuro/patologia , Nascimento Prematuro/prevenção & controle , Inibidores de Proteínas Quinases/administração & dosagem , Carneiro Doméstico , Tiofenos/administração & dosagem , Austrália Ocidental , Zearalenona/administração & dosagem , Zearalenona/uso terapêuticoRESUMO
Recently, regenerative medicine using the transplantation of embryonic stem cells and bone marrow stem cells has been a great success but still has many unconfirmed problems including its clinical evaluation. The aim of this article is to review current literature and some patents regarding molecular therapeutic agents including using MAP kinase TNNI3K for the treatment and diagnosis of acute myocardial ischemia or infarction. TNNI3K is a novel cardiac troponin I-interacting kinase gene and its overexpression may promote cardiac myogenesis, improve cardiac performance, and attenuate ischemia-induced ventricular remodeling. The modulation of embryonal stem cells with high TNNI3K activity using a TNNI3K active peptide could be a useful therapeutic approach for ischemic cardiac diseases. For overexpressing TNNI3K or enhancing TNNI3K activity in cardiac precursor cells, the engraftment of bone marrow cells or embryonic stem cells can effectively promote cardiac myogenesis, beating frequency, and contractile functions, and decrease "silent" (no contraction) cardiac cells after cell transplantion, indicating that the overexpression of TNNI3K can increase the success rate of transplanting embryonic stem cells or bone marrow cells into ischemic hearts for the treatment of ischemic cardiac diseases. Although previous investigations showing that TNNI3K may be involved in the development of cardiac hypertrophy, it is still unclear whether TNNI3K has a role in cardiac hypertrophy or what mechanism is involved in the effects of TNNI3K. To confirm this, further investigations need to be undertaken.