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1.
bioRxiv ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33269349

RESUMO

The SARS-CoV-2 macrodomain (Mac1) within the non-structural protein 3 (Nsp3) counteracts host-mediated antiviral ADP-ribosylation signalling. This enzyme is a promising antiviral target because catalytic mutations render viruses non-pathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of diverse fragment libraries resulted in 214 unique macrodomain-binding fragments, out of 2,683 screened. An additional 60 molecules were selected from docking over 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several crystallographic and docking fragment hits were validated for solution binding using three biophysical techniques (DSF, HTRF, ITC). Overall, the 234 fragment structures presented explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.

2.
Cancer Res ; 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33323380

RESUMO

Poly(ADP-ribose) polymerase (PARP) inhibitors are approved for treatment of cancers with BRCA1 or BRCA2 defects. In this study, we prepared and characterized a very long-acting PARP inhibitor. Synthesis of a macromolecular prodrug of talazoparib (TLZ) was achieved by covalent conjugation to a PEG40kDa carrier via a ß-eliminative releasable linker. A single injection of the PEG~TLZ conjugate was as effective as ~30 daily oral doses of TLZ in growth suppression of homologous recombination-defective tumors in mouse xenografts. These included the KT-10 Wilms tumor with a PALB2 mutation, the BRCA1-deficient MX-1 triple-negative breast cancer, and the BRCA2-deficient DLD-1 colon cancer; the prodrug did not inhibit an isogenic DLD-1 tumor with wild-type BRCA2. Although the half-life of PEG~TLZ and released TLZ in the mouse was only ~1 day, the exposure of released TLZ from a single safe, effective dose of the prodrug exceeded that of oral TLZ given daily over one month. µPET/CT imaging showed high uptake and prolonged retention of an 89Zr-labeled surrogate of PEG~TLZ in the MX-1 BRCA1-deficient tumor. These data suggest that the long-lasting anti-tumor effect of the prodrug is due to a combination of its long t1/2, the high exposure of TLZ released from the prodrug, increased tumor sensitivity upon continued exposure, and tumor accumulation. Using pharmacokinetic parameters of TLZ in humans, we designed a long-acting PEG~TLZ for humans that may be superior in efficacy to daily oral TLZ and would be useful for treatment of PARP inhibitor-sensitive cancers in which oral medications are not tolerated.

3.
Gastroenterology ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33039466

RESUMO

BACKGROUND & AIMS: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. METHODS: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. RESULTS: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. CONCLUSIONS: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.

4.
Nat Commun ; 11(1): 5270, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077732

RESUMO

Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort (n = 64) in comparison with a non-cancer cohort (n = 243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function (GATA4, GATA6, PROX1, ONECUT1, MEIS2), and cancer pathogenesis (YAP1, TEAD1, PROX1, IGF1). cfDNA hydroxymethylome in PDAC cohort is differentially enriched for genes that are commonly de-regulated in PDAC tumors upon activation of KRAS and inactivation of TP53. Regularized regression models built using 5hmC densities in genes perform with AUC of 0.92 (discovery dataset, n = 79) and 0.92-0.94 (two independent test sets, n = 228). Furthermore, tissue-derived 5hmC features can be used to classify PDAC cfDNA (AUC = 0.88). These findings suggest that 5hmC changes enable classification of PDAC even during early stage disease.


Assuntos
5-Metilcitosina/análogos & derivados , Ácidos Nucleicos Livres/metabolismo , Neoplasias Pancreáticas/genética , 5-Metilcitosina/metabolismo , Adulto , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
5.
Clin Cancer Res ; 26(23): 6204-6214, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32967941

RESUMO

PURPOSE: Autoantibody responses in cancer are of great interest, as they may be concordant with T-cell responses to cancer antigens or predictive of response to cancer immunotherapies. Thus, we sought to characterize the antibody landscape of metastatic castration-resistant prostate cancer (mCRPC). EXPERIMENTAL DESIGN: Serum antibody epitope repertoire analysis (SERA) was performed on patient serum to identify tumor-specific neoepitopes. Somatic mutation-specific neoepitopes were investigated by associating serum epitope enrichment scores with whole-genome sequencing results from paired solid tumor metastasis biopsies and germline blood samples. A protein-based immunome-wide association study (PIWAS) was performed to identify significantly enriched epitopes, and candidate serum antibodies enriched in select patients were validated by ELISA profiling. A distinct cohort of patients with melanoma was evaluated to validate the top cancer-specific epitopes. RESULTS: SERA was performed on 1,229 serum samples obtained from 72 men with mCRPC and 1,157 healthy control patients. Twenty-nine of 6,636 somatic mutations (0.44%) were associated with an antibody response specific to the mutated peptide. PIWAS analyses identified motifs in 11 proteins, including NY-ESO-1 and HERVK-113, as immunogenic in mCRPC, and ELISA confirmed serum antibody enrichment in candidate patients. Confirmatory PIWAS, Identifying Motifs Using Next-generation sequencing Experiments (IMUNE), and ELISA analyses performed on serum samples from 106 patients with melanoma similarly revealed enriched cancer-specific antibody responses to NY-ESO-1. CONCLUSIONS: We present the first large-scale profiling of autoantibodies in advanced prostate cancer, utilizing a new antibody profiling approach to reveal novel cancer-specific antigens and epitopes. Our study recovers antigens of known importance and identifies novel tumor-specific epitopes of translational interest.

6.
J Natl Cancer Inst ; 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32785646

RESUMO

BACKGROUND: The aetiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC. METHODS: We performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score (PRS) and MBC. All statistical tests were two-sided. RESULTS: The GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 x 10-30). CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic aetiology with FBC and identifying a four-fold high risk group of susceptible men.

7.
Breast Cancer Res Treat ; 183(3): 565-575, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32696317

RESUMO

BACKGROUND: Breast cancer (BCa) mortality is decreasing with early detection and improvement in therapies. The incidence of BCa, however, continues to increase, particularly estrogen-receptor-positive (ER +) subtypes. One of the greatest modifiers of ER + BCa risk is childbearing (parity), with BCa risk halved in young multiparous mothers. Despite convincing epidemiological data, the biology that underpins this protection remains unclear. Parity-induced protection has been postulated to be due to a decrease in mammary stem cells (MaSCs); however, reports to date have provided conflicting data. METHODS: We have completed rigorous functional testing of repopulating activity in parous mice using unfractionated and MaSC (CD24midCD49fhi)-enriched populations. We also developed a novel serial transplant method to enable us to assess self-renewal of MaSC following pregnancy. Lastly, as each pregnancy confers additional BCa protection, we subjected mice to multiple rounds of pregnancy to assess whether additional pregnancies impact MaSC activity. RESULTS: Here, we report that while repopulating activity in the mammary gland is reduced by parity in the unfractionated gland, it is not due to a loss in the classically defined MaSC (CD24+CD49fhi) numbers or function. Self-renewal was unaffected by parity and additional rounds of pregnancy also did not lead to a decrease in MaSC activity. CONCLUSIONS: Our data show instead that parity impacts on the stem-like activity of cells outside the MaSC population.

8.
Cancers (Basel) ; 12(6)2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32585905

RESUMO

Klotho was first discovered as an anti-ageing protein linked to a number of age-related disease processes, including cardiovascular, renal, musculoskeletal, and neurodegenerative conditions. Emerging research has also demonstrated a potential therapeutic role for Klotho in cancer biology, which is perhaps unsurprising given that cancer and ageing share similar molecular hallmarks. In addition to functioning as a tumour suppressor in numerous solid tumours and haematological malignancies, Klotho represents a candidate therapeutic target for patients with these diseases, the majority of whom have limited treatment options. Here, we examine contemporary evidence evaluating the anti-neoplastic effects of Klotho and describe the modulation of downstream oncogenic signalling pathways, including Wnt/ß-catenin, FGF, IGF1, PIK3K/AKT, TGFß, and the Unfolded Protein Response. We also discuss possible approaches to developing therapeutic Klotho and consider technological advances that may facilitate the delivery of Klotho through gene therapy.

9.
Cell Rep ; 31(6): 107625, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32402285

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3ß) a key regulator of glycolysis. Pharmacological inhibition of GSK3ß results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3ß inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.

10.
Nat Commun ; 11(1): 1446, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221288

RESUMO

Circulating tumour DNA (ctDNA) allows tracking of the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. However, exploiting ctDNA to determine how a patient's cancer is evolving in order to aid clinical decisions remains difficult. This is because ctDNA is a mix of fragmented alleles, and the contribution of different cancer deposits to ctDNA is largely unknown. Profiling ctDNA almost invariably requires prior knowledge of what genomic alterations to track. Here, we leverage on a rapid autopsy programme to demonstrate that unbiased genomic characterisation of several metastatic sites and concomitant ctDNA profiling at whole-genome resolution reveals the extent to which ctDNA is representative of widespread disease. We also present a methylation profiling method that allows tracking evolutionary changes in ctDNA at single-molecule resolution without prior knowledge. These results have critical implications for the use of liquid biopsies to monitor cancer evolution in humans and guide treatment.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , DNA Tumoral Circulante/genética , Epigênese Genética , Neoplasias da Mama/sangue , Evolução Clonal , Células Clonais , Metilação de DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Genoma Humano , Humanos , Metástase Neoplásica
11.
Gynecol Oncol ; 157(1): 55-61, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32139151

RESUMO

OBJECTIVE: Endometrioid ovarian carcinoma (EOVC) is an uncommon subtype of epithelial ovarian carcinoma and its molecular characteristics have been incompletely described. Prior sequencing investigations have been limited to targeted gene panels. We performed whole-exome sequencing to build an unbiased genetic profile of molecular alterations in endometrioid ovarian tumors with a goal to better understand this disease in the context of epithelial ovarian cancer and endometrioid uterine cancers. METHODS: Whole-exome sequencing was performed on EOVC samples (n = 26) and matched normals (n = 15). Gene mutations, mutational signatures and copy number variations (CNVs) informed a multi-dimensional regression classifier allowing for comparison to endometrial carcinoma (UCEC) and high grade serous ovarian carcinoma (HGSC). RESULTS: EOVC has a distinct and heterogeneous genomic profile. Identified significantly mutated genes in EOVC (PTEN, CTNNB1, PIK3CA, KMT2D, KMT2B, PIK3R1, ARID1A and TP53) occurred at similar frequencies in UCEC. Hypermutation, resulting from both mismatch repair deficiency (MMRd) and POLE mutation, was observed in EOVC at a frequency similar to UCEC. Like UCEC, a subset of EOVC cases closely resembled HGSC, harboring TP53 mutations, homologous recombination deficiency (HRd) mutation signatures and widespread CNVs. A machine-learning classifier confirmed the heterogeneous composition of EOVC. Potential therapeutic targets were identified in 62% of EOVC cases. We validated our findings in an orthogonal clinical sequencing registry of EOVC cases. CONCLUSIONS: We identified that EOVC are a molecularly heterogeneous group of epithelial ovarian cancers with distinct mutational signatures. In an age of precision oncology, there is a pressing need to understand the unique molecular drivers in uncommon histologic subtypes to facilitate genomically driven oncologic treatments.


Assuntos
Carcinoma Endometrioide/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Carcinoma Endometrioide/sangue , Carcinoma Endometrioide/patologia , Análise Mutacional de DNA , Feminino , Dosagem de Genes , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Sequenciamento Completo do Exoma
12.
Cancer Discov ; 10(3): 351-370, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071145

RESUMO

Drugs targeting the cell cycle-regulatory cyclin-dependent kinase (CDK) 4 and 6 have been approved for the treatment of hormone receptor-positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Another class of CDKs, the transcription-associated CDKs, including CDK7, CDK8, CDK9, CDK12 and CDK13, are critical regulators of gene expression. Recent evidence suggests several novel functions of these CDKs, including regulation of epigenetic modifications, intronic polyadenylation, DNA-damage responses, and genomic stability. Here, we summarize our current understanding of the transcriptional CDKs, their utility as biomarkers, and their potential as therapeutic targets. SIGNIFICANCE: CDK inhibitors targeting CDK4 and CDK6 have been approved in hormone receptor-positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Several studies now point to potential therapeutic opportunities by inhibiting the transcription-associated CDKs as well as therapeutic vulnerabilities with PARP inhibitors and immunotherapy in tumors deficient in these CDKs.

13.
Breast Cancer Res ; 22(1): 19, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046759

RESUMO

As a consequence of responding to colleagues who asked about the publication of the original article [1], the authors have determined that the data published in Table 4 of the paper are incorrect.

14.
Nat Commun ; 11(1): 312, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949161

RESUMO

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.


Assuntos
Neoplasias da Mama/genética , Variação Genética , Estudo de Associação Genômica Ampla , Células Germinativas , Apoptose , Relógios Circadianos , Biologia Computacional , Feminino , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Redes Reguladoras de Genes , Genótipo , Humanos , Prognóstico , Receptores Estrogênicos/genética , Transdução de Sinais
15.
Artif Organs ; 44(7): 709-716, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31970800

RESUMO

Only a small number of English hospitals provide postcardiotomy venoarterial extracorporeal membrane oxygenation (VA-ECMO) and there are doubts about its efficacy and safety. The aim of this service evaluation was to determine local survival rates and report on patient demographics. This was a retrospective service evaluation of prospectively recorded routine clinical data from a tertiary cardiothoracic center in the United Kingdom offering services including cardiac and thoracic surgery, heart and lung transplantation, venovenous extracorporeal membrane oxygenation (VV-ECMO) for respiratory failure, and all types of mechanical circulatory support. In six years, 39 patients were supported with VA-ECMO for refractory postcardiotomy cardiogenic shock (PCCS). We analyzed survival data and looked for associations between survival rates and patient characteristics. The intervention was venoarterial-ECMO in patients with PCCS either following weaning from cardiopulmonary bypass or following a trial of inotropes and intra-aortic balloon counterpulsation on the intensive care unit. 30-day, hospital discharge, 1-year and 2-year survivals were 51.3%, 41%, 37.5%, and 38.5%, respectively. The median (IQR [range]) duration of support was 6 (4-9 [1-35]) days. Nonsurvival was associated with advanced age, shorter intensive care length of stay, and the requirement for postoperative hemofiltration. Reasonable survival rates can be achieved in selected patients who may have been expected to have a worse mortality without VA-ECMO. We suggest postoperative VA-ECMO should be available to all patients undergoing cardiac surgery be it in their own center or through an established pathway to a specialist center.

16.
Nat Rev Drug Discov ; 19(1): 23-38, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31712683

RESUMO

The first wave of genetically targeted therapies for cancer focused on drugging gene products that are recurrently mutated in specific cancer types. However, mutational analysis of tumours has largely been exhausted as a strategy for the identification of new cancer targets that are druggable with conventional approaches. Furthermore, some known genetic drivers of cancer have not been directly targeted yet owing to their molecular structure (undruggable oncogenes) or because they result in functional loss (tumour suppressor genes). Functional genomic screening based on the genetic concept of synthetic lethality provides an avenue to discover drug targets in all these areas. Although synthetic lethality is not a new idea, recent advances, including CRISPR-based gene editing, have made possible systematic screens for synthetic lethal drug targets in human cancers. Such approaches have broad potential to drive the discovery of the next wave of genetic cancer targets and ultimately the introduction of effective medicines that are still needed for most cancers.


Assuntos
Antineoplásicos/uso terapêutico , Descoberta de Drogas , Edição de Genes , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Mutações Sintéticas Letais/efeitos dos fármacos , Terapia Genética , Humanos , Proteínas de Neoplasias/genética , Neoplasias/genética
18.
Int J Mol Sci ; 20(18)2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546756

RESUMO

Accelerated vascular aging is a condition that occurs as a complication of several highly prevalent inflammatory conditions such as chronic kidney disease, cancer, HIV infection and diabetes. Age-associated vascular alterations underlie a continuum of expression toward clinically overt cardiovascular disease. This has contributed to the striking epidemiologic transition whereby such noncommunicable diseases have taken center stage as modern-day global epidemics and public health problems. The identification of α-Klotho, a remarkable protein that confers powerful anti-aging properties has stimulated significant interest. In fact, emerging data have provided fundamental rationale for Klotho-based therapeutic intervention for vascular diseases and multiple other potential indications. However, the application of such discoveries in Klotho research remains fragmented due to significant gaps in our molecular understanding of Klotho biology, as well as hurdles in clinical research and experimental barriers that must first be overcome. These advances will be critical to establish the scientific platform from which future Klotho-based interventional trials and therapeutic enterprises can be successfully launched.


Assuntos
Envelhecimento/metabolismo , Glucuronidase/metabolismo , Doenças Vasculares/metabolismo , Envelhecimento/patologia , Animais , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Diabetes Mellitus/terapia , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/terapia , Doenças Vasculares/patologia , Doenças Vasculares/terapia
19.
PLoS One ; 14(9): e0223041, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31536587

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0004264.].

20.
Clin Cancer Res ; 25(18): 5608-5622, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31266829

RESUMO

PURPOSE: Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression.Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and long-term clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo. RESULTS: DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription. CONCLUSIONS: Our data show that DNAPK drives prostate cancer progression through transcriptional regulation of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.


Assuntos
Proteína Quinase Ativada por DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Transcrição Genética , Via de Sinalização Wnt , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteína Quinase Ativada por DNA/genética , Modelos Animais de Doenças , Progressão da Doença , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Masculino , Camundongos , Metástase Neoplásica , Fenótipo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Ligação Proteica , RNA Interferente Pequeno/genética
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