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BACKGROUND: Primary resistance to anti-EGFR therapies affects 40% of metastatic colorectal cancer patients harbouring wild-type RAS/RAF. YAP1 activation is associated with this resistance, prompting an investigation into AURKA's role in mediating YAP1 phosphorylation at Ser397, as observed in breast cancer. METHODS: We used transcriptomic analysis along with in vitro and in vivo models of RAS/RAF wild-type CRC to study YAP1 Ser397 phosphorylation as a potential biomarker for cetuximab resistance. We assessed cetuximab efficacy using CCK8 proliferation assays and cell cycle analysis. Additionally, we examined the effects of AURKA inhibition with alisertib and created a dominant-negative YAP1 Ser397 mutant to assess its impact on cancer stem cell features. RESULTS: The RAS/RAF wild-type CRC models exhibiting primary resistance to cetuximab prominently displayed elevated YAP1 phosphorylation at Ser397 primarily mediated by AURKA. AURKA-induced YAP1 phosphorylation was identified as a key trigger for cancer stem cell reprogramming. Consequently, we found that AURKA inhibition had the capacity to effectively restore cetuximab sensitivity and concurrently suppress the cancer stem cell phenotype. CONCLUSIONS: AURKA inhibition holds promise as a therapeutic approach to overcome cetuximab resistance in RAS/RAF wild-type colorectal cancer, offering a potential means to counter the development of cancer stem cell phenotypes associated with cetuximab resistance.
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Aurora Quinase A , Neoplasias Colorretais , Humanos , Cetuximab/farmacologia , Cetuximab/metabolismo , Aurora Quinase A/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
BACKGROUND: Galectin-1 (Gal-1) plays major roles in cancer by modulating different processes leading to tumor development and progression. In the last years, it has been suggested as a promising target for anticancer therapy. Recently, aflibercept has shown high affinity for Gal-1. Here, we investigated how aflibercept could exert its antitumor activity via Gal-1-driven pathways in neuroendocrine carcinomas (NECs). METHODS AND RESULTS: NEC tumor xenografts were used to assess the effect of aflibercept on Gal-1 functions. Aflibercept induced a significant reduction of Gal-1 at epithelial, stromal, and extracellular localizations in lung NEC, whereas this was not observed in colon NECs, which displayed low expression of Gal-1. Additionally, aflibercept significantly reduced p-VEGFR2 protein, extracellular matrix remodeling, epithelial-mesenchymal transition, and activation of cancer-associated fibroblast hampering cell invasion in lung NEC but not in colon NEC. Gal-1 screening in human NECs confirmed that pulmonary and pancreatic tumors displayed higher levels of Gal-1 than colon NECs, becoming good candidates to benefit from aflibercept treatment. CONCLUSIONS: The lack of validated predictive markers of aflibercept is a weakness for guaranteeing the best treatment management with this drug. This work provides new mechanistic insight of aflibercept depending on Gal-1. Thus, in tumors overexpressing Gal-1, aflibercept has not only an antiangiogenic effect but also prevents Gal-1-mediated tumor-stroma cross talk. The stronger aflibercept effect in tumors with high levels of Gal-1 points out this protein as a molecular marker to predict the efficacy of this agent not only for NECs but also for other tumors with high levels of this protein.
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Inibidores da Angiogênese/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Galectina 1/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Proteínas Recombinantes de Fusão/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Neuroendocrine carcinoma (NEC) is a rare and very aggressive tumor. It has been greatly understudied, and very little is known about optimal treatment strategy for patients with this disease. The purpose of this study was to evaluate in vivo whether anti-vascular endothelial growth factor (VEGF) drugs could be a therapeutic alternative for these tumors with a poor prognosis. METHODS: We have developed 2 xenograft models using either human cell line derived from lung (H460) or from colon (COLO320) NEC to assess the effect of 2 antiangiogenic drugs, aflibercept and bevacizumab, on tumor growth and their pathological characteristics. Additionally, tumors were subjected to immunohistochemistry staining and proteins were measured with Western blot and ELISA. RESULTS: Both aflibercept and bevacizumab showed significant antitumor activity (p < 0.001). In the H460 model, aflibercept resulted in 94% tumor growth inhibition (TGI) and bevacizumab treatment resulted in 72.2% TGI. Similarly, in the COLO320 model, aflibercept and bevacizumab resulted in 89.3 and 84% TGI, respectively. Moreover, antitumor activity occurs early after treatment initiation. Using Tumor Control Index score, which address the kinetics of tumor growth in a way comparable to the methods used in human clinical studies, we confirmed that both drugs inhibit significantly tumor growth. When tumor stabilization was evaluated, aflibercept shows higher ability to stabilize NEC tumors than bevacizumab. CONCLUSION: Results derived from this study strongly support anti-VEGF therapies, especially aflibercept, as a novel therapeutic option in NECs. Further studies are necessary, but our observations encourage the evaluation of antiangiogenics in clinical trials combined with standard chemotherapy.
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Inibidores da Angiogênese/farmacologia , Bevacizumab/farmacologia , Carcinoma Neuroendócrino/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacologia , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Receptores de Fatores de Crescimento do Endotélio VascularAssuntos
Proteínas Adaptadoras de Transdução de Sinal , Neoplasias , Proteínas de Sinalização YAP , Humanos , Fosforilação , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Serina/metabolismoRESUMO
Rectal cancer represents about 30% of colorectal cancers, being around 50% locally advanced at presentation. Chemoradiation (CRT) followed by total mesorectal excision is the standard of care for these locally advanced stages. However, it is not free of adverse effects and toxicity and the complete pathologic response rate is between 10% and 30%. This makes it extremely important to define factors that can predict response to this therapy. Focal adhesion kinase (FAK) expression has been correlated with worse prognosis in several tumours and its possible involvement in cancer radio- and chemosensitivity has been suggested; however, its role in rectal cancer has not been analysed yet. To analyse the association of FAK expression with tumour response to CRT in locally advanced rectal cancer. This study includes 73 patients with locally advanced rectal cancer receiving standard neoadjuvant CRT followed by total mesorectal excision. Focal adhesion kinase protein levels were immunohistochemically analysed in the pre-treatment biopsies of these patients and correlated with tumour response to CRT and patients survival. Low FAK expression was significantly correlated with local and distant recurrence (P = 0.013). Low FAK expression was found to be a predictive marker of tumour response to neoadjuvant therapy (P = 0.007) and patients whose tumours did not express FAK showed a strong association with lower disease-free survival (P = 0.01). Focal adhesion kinase expression predicts neoadjuvant CRT response in rectal cancer patients and it is a clinically relevant risk factor for local and distant recurrence.
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Quimiorradioterapia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Terapia Neoadjuvante , Recidiva Local de Neoplasia/patologia , Neoplasias Retais/enzimologia , Neoplasias Retais/terapia , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/patologia , Fatores de Risco , Análise Serial de Tecidos , Resultado do TratamentoRESUMO
BACKGROUND: Neoadjuvant chemoradiotherapy (NACRT) followed by surgical resection is the standard therapy for locally advanced rectal cancer. However, tumor response following NACRT varies, ranging from pathologic complete response to disease progression. We evaluated the kinases VRK1 and VRK2, which are known to play multiple roles in cellular proliferation, cell cycle regulation, and carcinogenesis, and as such are potential predictors of tumor response and may aid in identifying patients who could benefit from NACRT. METHODS: Sixty-seven pretreatment biopsies were examined for VRK1 and VRK2 expression using tissue microarrays. VRK1 and VRK2 Histoscores were combined by linear addition, resulting in a new variable designated as "composite score", and the statistical significance of this variable was assessed by univariate and multivariate logistic regression. The Hosmer-Lemeshow goodness-of-fit test and area under the ROC curve (AUC) analysis were carried out to evaluate calibration and discrimination, respectively. A nomogram was also developed. RESULTS: Univariate logistic regression showed that tumor size as well as composite score were statistically significant. Both variables remained significant in the multivariate analysis, obtaining an OR for tumor size of 0.65 (95 % CI, 0.45-0.94; p = 0.021) and composite score of 1.24 (95 % CI, 1.07-1.48; p = 0.005). Hosmer-Lemeshow test showed an adequate model calibration (p = 0.630) and good discrimination was also achieved, AUC 0.79 (95 % CI, 0.68-0.90). CONCLUSIONS: This study provides novel data on the role of VRK1 and VRK2 in predicting tumor response to NACRT, and we propose a model with high predictive ability which could have a substantial impact on clinical management of locally advanced rectal cancer.
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Adenocarcinoma/enzimologia , Biomarcadores Tumorais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias Retais/enzimologia , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Idoso , Área Sob a Curva , Quimiorradioterapia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Terapia Neoadjuvante , Curva ROC , Neoplasias Retais/mortalidade , Neoplasias Retais/terapia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: DEK is a transcription factor involved in stabilization of heterochromatin and cruciform structures. It plays an important role in development and progression of different types of cancer. This study aims to analyze the role of DEK in metastatic colorectal cancer. METHODS: Baseline DEK expression was firstly quantified in 9 colorectal cell lines and normal mucosa by WB. SiRNA-mediated DEK inhibition was carried out for transient DEK silencing in DLD1 and SW620 to dissect its role in colorectal cancer aggressiveness. Irinotecan response assays were performed with SN38 over 24 hours and apoptosis was quantified by flow cytometry. Ex-vivo assay was carried out with 3 fresh tumour tissues taken from surgical resection and treated with SN38 for 24 hours. DEK expression was determined by immunohistochemistry in 67 formalin-fixed paraffin-embedded tumour samples from metastatic colorectal cancer patients treated with irinotecan-based therapy as first-line treatment. RESULTS: The DEK oncogene is overexpressed in all colorectal cancer cell lines. Knock-down of DEK on DLD1 and SW620 cell lines decreased cell migration and increased irinotecan-induced apoptosis. In addition, low DEK expression level predicted irinotecan-based chemotherapy response in metastatic colorectal cancer patients with KRAS wild-type. CONCLUSIONS: These data suggest DEK overexpression as a crucial event for the emergence of an aggressive phenotype in colorectal cancer and its potential role as biomarker for irinotecan response in those patients with KRAS wild-type status.
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Antineoplásicos Fitogênicos/uso terapêutico , Biomarcadores Tumorais/fisiologia , Camptotecina/análogos & derivados , Proteínas Cromossômicas não Histona/fisiologia , Neoplasias Colorretais/tratamento farmacológico , Proteínas Oncogênicas/fisiologia , Adulto , Idoso , Apoptose , Biomarcadores Tumorais/análise , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Proteínas Cromossômicas não Histona/análise , Neoplasias Colorretais/química , Neoplasias Colorretais/patologia , Regulação para Baixo , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas/análise , Fenótipo , Proteínas de Ligação a Poli-ADP-Ribose , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genéticaRESUMO
In pancreatic ductal adenocarcinoma (PDAC), metabolic rewiring and resistance to standard therapy are closely associated. PDAC cells show enormous requirements for glucose-derived citrate, the first rate-limiting metabolite in the synthesis of new lipids. Both the expression and activity of citrate synthase (CS) are extraordinarily upregulated in PDAC. However, no previous relationship between gemcitabine response and citrate metabolism has been documented in pancreatic cancer. Here, we report for the first time that pharmacological doses of vitamin C are capable of exerting an inhibitory action on the activity of CS, reducing glucose-derived citrate levels. Moreover, ascorbate targets citrate metabolism towards the de novo lipogenesis pathway, impairing fatty acid synthase (FASN) and ATP citrate lyase (ACLY) expression. Lowered citrate availability was found to be directly associated with diminished proliferation and, remarkably, enhanced gemcitabine response. Moreover, the deregulated citrate-derived lipogenic pathway correlated with a remarkable decrease in extracellular pH through inhibition of lactate dehydrogenase (LDH) and overall reduced glycolytic metabolism. Modulation of citric acid metabolism in highly chemoresistant pancreatic adenocarcinoma, through molecules such as vitamin C, could be considered as a future clinical option to improve patient response to standard chemotherapy regimens.
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We have investigated the mechanism of action of inhibition of the choline kinase of P. falciparum (p.f.-ChoK) by two inhibitors of the human ChoKα, MN58b and RSM-932A, which have previously been shown to be potent antitumoral agents. The efficacy of these inhibitors against p.f.-ChoK is investigated using enzymatic and in vitro assays. While MN58b may enter the choline/phosphocholine binding site, RSM-932A appears to have an altogether novel mechanism of inhibition and is synergistic with respect to both choline and ATP. A model of inhibition for RSM-932A in which this inhibitor traps p.f.-ChoK in a phosphorylated intermediate state blocking phosphate transfer to choline is presented. Importantly, MN58b and RSM-932A have in vitro inhibitory activity in the low nanomolar range and are equally effective against chloroquine-sensitive and chloroquine-resistant strains. RSM-932A and MN58b significantly reduced parasitemia and induced the accumulation of trophozoites and schizonts, blocking intraerythrocytic development and interfering with parasite egress or invasion, suggesting a delay of the parasite maturation stage. The present data provide two new potent structures for the development of antimalarial compounds and validate p.f.-ChoK as an accessible drug target against the parasite.
Assuntos
Compostos de Anilina/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Butanos/farmacologia , Colina Quinase/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/antagonistas & inibidores , Compostos de Piridínio/farmacologia , Compostos de Quinolínio/farmacologia , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Cloroquina/farmacologia , Colina/química , Colina/metabolismo , Colina Quinase/química , Colina Quinase/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Escherichia coli/genética , Humanos , Cinética , Testes de Sensibilidade Parasitária , Fosforilação/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Plasmodium falciparum/crescimento & desenvolvimento , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Trofozoítos/efeitos dos fármacos , Trofozoítos/enzimologia , Trofozoítos/crescimento & desenvolvimentoRESUMO
Lung cancer is one of the main causes of death in developed countries, and non-small cell lung cancer (NSCLC) is the most frequent type (80% of patients). In advanced NSCLC, platinum-based chemotherapy is the frontline palliative treatment, but less than 5% of patients achieve prolonged survival. Immunotherapy has recently been proposed as the standard of care (SoC) as either monotherapy or in combination with chemotherapy for advanced NSCLC. The levels of expression of PD-L1 are the only predictive biomarkers for patient assessment. Although around 30% of patients receiving immunotherapy achieve 5-year survival, a significant number does not benefit from this novel therapeutic approach. Therefore, there is a need for novel strategies to improve clinical outcomes. The expression level of choline kinase α (ChoKα) is increased in a large number of human tumors, including NSCLC tumors, and constitutes an independent prognostic factor for early-stage NSCLC patients. Thus, ChoKα has been postulated as a new target drug in cancer therapy. The combination of cisplatin with novel targeted drugs such as choline kinase inhibitors may improve both the survival rates and the quality of life of NSCLC patients and may serve as the basis for the development of new therapeutic approaches. To that aim, we developed several in vitro and in vivo approaches to assess the antitumor activity of a novel combination regimen using cisplatin and ChoKα inhibitors. Our results suggest that a proper combination of specific inhibitors of the NSCLC prognostic factor ChoKα and platinum-based conventional chemotherapy might constitute a new, efficient treatment approach for NSCLC patients. This novel approach may help reduce the toxicity profile associated with cisplatin since, despite the advances in NSCLC management in recent years, the overall 5-year survival rate is still poor.
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INTRODUCTION: small-cell lung cancer (SCLC) is one of the most lethal malignancies. Its management is complex due to the lack of biomarkers and limited therapies. Galectin-1 (Gal-1) plays a major role in cancer development and progression. The aim of this study is to assess whether Gal-1 has a predictive role in the disease evolution and its therapeutic potential. MATERIAL AND METHODS: The expression level of Gal-1 was examined by using a public RNA-sequencing (77 SCLC patients) and in-house immunohistochemistry (IHC) performed on biopsies from 81 patients. Survival curves and Cox regression analysis were used to assess the prognostic potential of Gal-1. In addition, a SCLC-PDX model was carried out and treated with either OTX008, an inhibitor of Gal-1, or vehicle to assess the effects of Gal-1 inhibition on this disease in vivo. RESULTS: Galectin-1 gene (LGALS1) expression showed a strong negative correlation with outcome in SCLC patients with advanced disease (p = 0.007). IHC unveiled that overall survival (OS) was significantly lower among extensive-stage SCLC (ES-SCLC) patient group with increased level of Gal-1 and platelet-to-lymphocyte ratio (PLR) (HR=3.07, 95% CI: 1.62, 5.79, p < 0.001). The SCLC-PDX model showed a significant reduction in tumor size (tumor growth inhibition [TGI] index 73%) without side effects. DISCUSSION: in this study, high levels of Gal-1 and PLR were associated with poorer OS in SCLC patients, supporting their utility as clinical prognostic biomarkers. Moreover, the in vivo model suggests the inhibition of Gal-1 as a novel potential therapy for this disease with very poor prognosis.
Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Galectina 1/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Benzamidas , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Recent reviews pinpointed the enormous diversity of proteins found in living organisms, especially in higher eukaryotes. Protein diversity is driven through three main processes: first, at deoxyribonucleic acid (DNA) level (i.e. gene polymorphisms), second, at precursor messenger ribonucleic acid (pre-mRNA) or messenger ribonucleic acid (mRNA) level (i.e. alternative splicing, also termed as differential splicing) and, finally, at the protein level (i.e. PTM). Current proteomic technologies allow the identification, characterization and quantitation of up to several thousands of proteins in a single experiment. Nevertheless, the identification and characterization of protein species using these technologies are still hampered. Here, we review the use of the terms "protein species" and "protein isoform." We evidence that the appropriate selection of the database used for searches can impede or facilitate the identification of protein species. We also describe examples where protein identification search engines systematically fail in the attribution of protein species. We briefly review the characterization of protein species using proteomic technologies including gel-based, gel-free, bottom-up and top-down analysis and discuss their limitations. As an example, we discuss the theoretical characterization of the two human choline kinase species, α-1 and α-2, sharing the same catalytic activity but generated by alternative splicing on CHKA gene.
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Processamento de Proteína Pós-Traducional , Proteínas/química , Proteínas/metabolismo , Proteômica/métodos , Animais , Humanos , Isoformas de Proteínas , Proteínas/genética , Análise de Sequência de Proteína/métodosRESUMO
In the last decade, several reports have focused on the identification and characterization of proteins present in urine. In an effort to build a list of proteins of interest as biomarkers, we reviewed the largest urine proteomes and built two updated lists of proteins of interest (available as supplementary tables). The first table includes a consensus list of 443 proteins found in urine by independent laboratories and reported on the top three largest urine proteomes currently published. This consensus list of proteins could serve as biomarkers to diagnose, monitor and manage a number of diseases. Here, we focus on a reduced list of 35 proteins with potential interest as cancer biomarkers in urine following two criteria: first, proteins previously detected in urine using bottom-up proteomic experiments, and second, those suggested as cancer protein biomarkers in human plasma. In an effort to standardize the information presented and its use in future studies, here we include the updated International Protein Index (v. 3.80) and primary Swiss-Prot accession numbers, official gene symbols and recommended full names. The main variables that influence urine proteomic experiments are also discussed.
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Biomarcadores Tumorais/urina , Neoplasias/metabolismo , Neoplasias/urina , Proteômica/métodos , HumanosRESUMO
Colorectal cancer remains among the cancers with the highest incidence, prevalence, and mortality worldwide. Although the development of targeted therapies against the EGFR and VEGFR membrane receptors has considerably improved survival in these patients, the appearance of resistance means that their success is still limited. Overactivation of several members of the Ras-GTPase family is one of the main actors in both tumour progression and the lack of response to cytotoxic and targeted therapies. This fact has led many resources to be devoted over the last decades to the development of targeted therapies against these proteins. However, they have not been as successful as expected in their move to the clinic so far. In this review, we will analyse the role of these Ras-GTPases in the emergence and development of colorectal cancer and their relationship with resistance to targeted therapies, as well as the status and new advances in the design of targeted therapies against these proteins and their possible clinical implications.
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New therapeutic targets are revolutionizing colorectal cancer clinical management, opening new horizons in metastatic patients' outcome. Polo Like Kinase1 (PLK1) inhibitors have high potential as antitumoral agents, however, the emergence of drug resistance is a major challenge for their use in clinical practice. Overcoming this challenge represents a hot topic in current drug discovery research. BI2536-resistant colorectal cancer cell lines HT29R, RKOR, SW837R and HCT116R, were generated in vitro and validated by IG50 assays and xenografts models by the T/C ratio. Exons 1 and 2 of PLK1 gene were sequenced by Sanger method. AXL pathway, Epithelial-to-Mesenchymal transition (EMT) and Multidrug Resistance (MDR1) were studied by qPCR and western blot in resistant cells. Simvastatin as a re-sensitizer drug was tested in vitro and the drug combination strategies were validated in vitro and in vivo. PLK1 gene mutation R136G was found for RKOR. AXL pathway trough TWIST1 transcription factor was identified as one of the mechanisms involved in HT29R, SW837R and HCT116R lines, inducing EMT and upregulation of MDR1. Simvastatin was able to impair the mechanisms activated by adaptive resistance and its combination with BI2536 re-sensitized resistant cells in vitro and in vivo. Targeting the mevalonate pathway contributes to re-sensitizing BI2536-resistant cells in vitro and in vivo, raising as a new strategy for the clinical management of PLK1 inhibitors.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Ácido Mevalônico/metabolismo , Proteínas Nucleares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Sinvastatina/farmacologia , Proteína 1 Relacionada a Twist/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Células HCT116 , Células HT29 , Humanos , Camundongos Nus , Mutação , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais , Proteína 1 Relacionada a Twist/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Receptor Tirosina Quinase Axl , Quinase 1 Polo-LikeRESUMO
To date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to RET signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (n = 266) and controls (n = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene- and linkage disequilibrium-based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (STAT1, AURKA, BCL2, CDKN2B, CDK6, and COMT) consistently associated with sMTC risk in the two case-control series and a seventh (HRAS) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases.
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Carcinoma Medular/genética , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Medular/metabolismo , Estudos de Casos e Controles , Inibidor de Quinase Dependente de Ciclina p15/biossíntese , Inibidor de Quinase Dependente de Ciclina p15/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Penetrância , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-ret/metabolismo , Transdução de Sinais , Neoplasias da Glândula Tireoide/metabolismo , Transcrição GênicaRESUMO
Aging is associated with a higher risk of cancer, >70% of cancer-related deaths occur in aged patients; however, this population is underrepresented in clinical trials, therefore, clinical information regarding this age group is rather limited. OBJECTIVES: Neutrophil-to lymphocyte ratio (NLR) and platelet-to lymphocyte ratio (PLR) have been described as biomarkers in cancer, thus, we have assessed their impact in an aged cohort of patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: 110 patients with a mean age of 72.2â¯years at diagnosis were retrospectively reviewed; NLR and PLR were calculated and dichotomized using a cutoff point estimated by a ROC curve. Survival curves and Cox regression analysis were performed to assess the prognostic potential of ratios in terms of progression free survival (PFS) and overall survival (OS). RESULTS: High NLR was associated to worse outcome in terms of PFS (ten vs sixteen months; Log rank <0.001) (HR 2.00 95%CI 1. 29-3.11; pâ¯=â¯.002) and OS (20 vs 26â¯months; Log rank 0.002) (HR 2.28 95%CI 1.40-3.71; pâ¯=â¯.001). Similarly it occurs with high PLR and PFS (nine vs fifteen months; Log rank 0.04) (HR 1.55 95%CI 1.01-2.40; pâ¯=â¯.04) and OS (nineteen vs 25â¯months; Log rank <0.001) (HR 2.35 95%CI 1.45-3.80; pâ¯<â¯.001). CONCLUSION: This study confirms the role of NLR and PLR as accessible and noninvasive biomarkers that could be use as a routine tool in the clinical practice in geriatric patients with mCRC.
Assuntos
Neoplasias Colorretais/sangue , Contagem de Linfócitos , Neutrófilos , Contagem de Plaquetas , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Humanos , Contagem de Leucócitos , Masculino , Metástase Neoplásica , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Germ line missense mutations in the RET proto-oncogene are responsible for the inherited cancer syndrome multiple endocrine neoplasia type 2A (MEN2A). The clinical presentation of the disease and the age at onset varies even within families, where patients carry the same mutation. These variations in phenotypes suggest a role for genetic modifiers, and recently, it has been reported that polymorphisms within RET (G691S/S904S) may have such a modifier effect on the age at onset. Here, we investigate whether this observed association could be confirmed in a larger set of 384 individuals from MEN2 families from four different European populations. In addition, we tested as modifiers four other single nucleotide polymorphisms (SNPs), which we have found in a previous association study of RET, its coreceptors, and ligands to be associated with the risk of developing sporadic medullary thyroid carcinoma. We could not replicate the association between G691S/S904S and modifier effects in MEN2A families in any of the four European families analyzed. Of the other SNPs tested, only RET A432A showed a positive weak effect on tumor spectrum within MEN2A, which requires replication in a larger series.
Assuntos
Neoplasia Endócrina Múltipla Tipo 2a/genética , Proteínas Proto-Oncogênicas c-ret/genética , Adulto , Idade de Início , Carcinoma Medular/genética , Feminino , Predisposição Genética para Doença , Genótipo , Mutação em Linhagem Germinativa , Humanos , Ligantes , Masculino , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Proto-Oncogene Mas , Receptores de Superfície Celular/genética , Neoplasias da Glândula Tireoide/genética , População Branca/genéticaRESUMO
It is generally believed that the initiation of breast cancer is a consequence of cumulative genetic damage leading to genetic alterations and provoking uncontrolled cellular proliferation and/or aberrant programmed cell death, or apoptosis. Reactive oxygen species have been related to the etiology of cancer as they are known to be mitogenic and therefore capable of tumor promotion. The aim of this study was to assess the role of common variation in 10 polymorphic genes coding for antioxidant defense enzymes in modulating individual susceptibility to breast cancer using a case-control study (N cases = 4,474 and N controls = 4,580). Both cases and controls were from the East Anglian region of the United Kingdom. We have identified a set of 54 single nucleotide polymorphisms (SNPs) that efficiently tag all the known SNPs in the 10 genes and are also expected to tag any unknown SNPs in each gene. We found no evidence for association of common variants in SOD1, SOD2, GPX1, GPX4, GSR, TXNRD1, and TXN2. There was borderline evidence for association of variants in CAT g27168a {P [2 degrees of freedom (df)] = 0.05}, TXN t2715c [P (2 df) = 0.007], and TXNRD2 A66S and TXNRD2 g23524a (P(trend) = 0.074 and 0.046, respectively). For TXNRD2 A66S [AS versus AA: odds ratio (OR), 1.05; 95% confidence intervals (95% CI), 0.96-1.15; SS versus AA: OR, 1.12; 95% CI, 0.98-1.29], there are bioinformatics data to suggest that it is functional but confirmation in independent data sets is required before they can be regarded as definitive breast cancer susceptibility alleles. Even if confirmed, these four alleles would account for just 0.32% of the excess familial risk of breast cancer.