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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND: High tumor mutation burden (TMB-H) has been proposed as a predictive biomarker for response to immune checkpoint blockade (ICB), largely due to the potential for tumor mutations to generate immunogenic neoantigens. Despite recent pan-cancer approval of ICB treatment for any TMB-H tumor, as assessed by the targeted FoundationOne CDx assay in nine tumor types, the utility of this biomarker has not been fully demonstrated across all cancers. PATIENTS AND METHODS: Data from over 10 000 patient tumors included in The Cancer Genome Atlas were used to compare approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells. Association of TMB with ICB treatment outcomes was analyzed by both objective response rates (ORRs, N = 1551) and overall survival (OS, N = 1936). RESULTS: In cancer types where CD8 T-cell levels positively correlated with neoantigen load, such as melanoma, lung, and bladder cancers, TMB-H tumors exhibited a 39.8% ORR to ICB [95% confidence interval (CI) 34.9-44.8], which was significantly higher than that observed in low TMB (TMB-L) tumors [odds ratio (OR) = 4.1, 95% CI 2.9-5.8, P < 2 × 10-16]. In cancer types that showed no relationship between CD8 T-cell levels and neoantigen load, such as breast cancer, prostate cancer, and glioma, TMB-H tumors failed to achieve a 20% ORR (ORR = 15.3%, 95% CI 9.2-23.4, P = 0.95), and exhibited a significantly lower ORR relative to TMB-L tumors (OR = 0.46, 95% CI 0.24-0.88, P = 0.02). Bulk ORRs were not significantly different between the two categories of tumors (P = 0.10) for patient cohorts assessed. Equivalent results were obtained by analyzing OS and by treating TMB as a continuous variable. CONCLUSIONS: Our analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type-specific studies are warranted.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Biomarcadores de Tumor , Humanos , Masculino , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Resultado del TratamientoRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor-receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy. PATIENTS AND METHODS: This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan-Meier method were used. RESULTS: Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti-programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity. CONCLUSIONS: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.
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Carcinoma de Células Renales/tratamiento farmacológico , Inmunoterapia/métodos , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/farmacología , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Cabozantinib prolongs overall survival (OS) and progression-free survival (PFS) in patients with metastatic clear cell renal cell carcinoma (RCC) that progressed on first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI). The role of cabozantinib has not been established in non-clear cell renal cell carcinoma (nccRCC). METHODS: This is a retrospective study of 30 patients with nccRCC who received cabozantinib from January 2013 to January 2017. Information collected included baseline characteristics, toxicity, dose reductions, PFS and OS. A fellowship trained abdominal radiologist, blinded to patient history and clinical data, assessed radiographic response using RECIST, v1.1. RESULTS: With a median follow-up of 20.6 months (95% confidence interval [CI]: 11.4-28.8), median PFS was 8.6 months (95% CI: 6.1-14.7), and median OS was 25.4 months (95% CI: 15.5-35.4). Of the 28 patients with measurable disease, 4 had partial responses (2 papillary, 1 chromophobe and 1 unclassified RCC), 18 had stable disease (64.2%) and 6 had progressive disease (21.4%), resulting in a 14.3% objective response rate and a 78.6% disease control rate. Two patients with papillary RCC who had experienced disease progression on savolitinib achieved durable partial response and stable disease, respectively, following treatment with cabozantinib. Of the 21 patients who started cabozantinib at 60 mg/d, 12 (57.1%) required dose reduction due to toxicity. CONCLUSION: In this retrospective study, cabozantinib produced a clinically meaningful benefit in patients with metastatic nccRCC, the majority of whom had disease progression on prior VEGFR-TKIs. Prospective trials of cabozantinib in nccRCC are warranted.
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Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/secundario , Neoplasias Renales/tratamiento farmacológico , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anilidas/administración & dosificación , Anilidas/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/enzimología , Diarrea/inducido químicamente , Fatiga/inducido químicamente , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Neoplasias Renales/enzimología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/efectos adversos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/genética , Piridinas/administración & dosificación , Piridinas/efectos adversos , Estudios Retrospectivos , Terapia RecuperativaRESUMEN
The hypoxia-regulated tumor-suppressor von Hippel-Lindau (VHL) is an E3 ligase that recognizes its substrates as part of an oxygen-dependent prolyl hydroxylase (PHD) reaction, with hypoxia-inducible factor α (HIFα) being its most notable substrate. Here we report that VHL has an equally important function distinct from its hypoxia-regulated activity. We find that Aurora kinase A (AURKA) is a novel, hypoxia-independent target for VHL ubiquitination. In contrast to its hypoxia-regulated activity, VHL mono-, rather than poly-ubiquitinates AURKA, in a PHD-independent reaction targeting AURKA for degradation in quiescent cells, where degradation of AURKA is required to maintain the primary cilium. Tumor-associated variants of VHL differentiate between these two functions, as a pathogenic VHL mutant that retains intrinsic ability to ubiquitinate HIFα is unable to ubiquitinate AURKA. Together, these data identify VHL as an E3 ligase with important cellular functions under both normoxic and hypoxic conditions.
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Aurora Quinasa A/metabolismo , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Carcinoma de Células Renales/genética , Hipoxia de la Célula , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genética , Mutación , Ubiquitinación , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genéticaRESUMEN
Background: Activation of the phosphoinisitide-3 kinase (PI3K) pathway through mutation and constitutive upregulation has been described in renal cell carcinoma (RCC), making it an attractive target for therapeutic intervention. We performed a randomized phase II study in vascular endothelial growth factor (VEGF) therapy refractory patients to determine whether MK-2206, an allosteric inhibitor of AKT, was more efficacious than the mammalian target of rapamycin inhibitor everolimus. Patients and methods: A total of 43 patients were randomized in a 2:1 distribution, with 29 patients assigned to the MK-2206 arm and 14 to the everolimus arm. Progression-free survival (PFS) was the primary endpoint. Results: The trial was closed at the first futility analysis with an observed PFS of 3.68 months in the MK-2206 arm and 5.98 months in the everolimus arm. Dichotomous response rate profiles were seen in the MK-2206 arm with one complete response and three partial responses in the MK-2206 arm versus none in the everolimus arm. On the other hand, progressive disease was best response in 44.8% of MK2206 versus 14.3% of everolimus-treated patients. MK-2206 induced significantly more rash and pruritis than everolimus, and dose reduction occurred in 37.9% of MK-2206 versus 21.4% of everolimus-treated patients. Genomic analysis revealed that 57.1% of the patients in the PD group had either deleterious TP53 mutations or ATM mutations or deletions. In contrast, none of the patients in the non-PD group had TP53 or ATM defects. No predictive marker for response was observed in this small dataset. Conclusions: Dichotomous outcomes are observed when VEGF therapy refractory patients are treated with MK-2206, and MK-2206 does not demonstrate superiority to everolimus. Additionally, mutations in DNA repair genes are associated with early disease progression, indicating that dysregulation of DNA repair is associated with a more aggressive tumor phenotype in RCC.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Everolimus/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Loss of von Hippel Lindau (VHL) protein function is a key driver of VHL diseases, including sporadic and inherited clear cell renal cell carcinoma. Modulation of the proteostasis of VHL, especially missense point-mutated VHL, is a promising approach to augmenting VHL levels and function. VHL proteostasis is regulated by multiple mechanisms including folding, chaperone binding, complex formation and phosphorylation. Nevertheless, many details underlying the regulations of VHL proteostasis are unknown. VHL is expressed as two variants, VHL30 and VHL19. Furthermore, the long-form variant of VHL was often detected as multiple bands by western blotting. However, how these multiple species of VHL are generated and whether the process regulates VHL proteostasis and function are unknown. We hypothesized that the two major species are generated by VHL protein cleavage, and the cleavage regulates VHL proteostasis and subsequent function. We characterized VHL species using genetical and pharmacological approaches and showed that VHL was first cleaved at the N-terminus by chymotrypsin C before being directed for proteasomal degradation. Casein kinase 2-mediated phosphorylation at VHL N-terminus was required for the cleavage. Furthermore, inhibition of cleavage stabilized VHL protein and thereby promoted HIF downregulation. Our study reveals a novel mechanism regulating VHL proteostasis and function, which is significant for identifying new drug targets and developing new therapeutic approaches targeting VHL deficiency in VHL diseases.
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Carcinoma de Células Renales/genética , Isoformas de Proteínas/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Enfermedad de von Hippel-Lindau/genética , Carcinoma de Células Renales/patología , Quinasa de la Caseína II/genética , Quinasa de la Caseína II/metabolismo , Línea Celular Tumoral , Quimotripsina/química , Regulación Neoplásica de la Expresión Génica , Humanos , Mutación , Fosforilación , Unión Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Proteolisis , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/química , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/patologíaRESUMEN
Mutations in SETD2, a histone H3 lysine trimethyltransferase, have been identified in clear cell renal cell carcinoma (ccRCC); however it is unclear if loss of SETD2 function alters the genomic distribution of histone 3 lysine 36 trimethylation (H3K36me3) in ccRCC. Furthermore, published epigenomic profiles are not specific to H3K36me3 or metastatic tumors. To determine if progressive SETD2 and H3K36me3 dysregulation occurs in metastatic tumors, H3K36me3, SETD2 copy number (CN) or SETD2 mRNA abundance was assessed in two independent cohorts: metastatic ccRCC (n=71) and the Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma data set (n=413). Although SETD2 CN loss occurs with high frequency (>90%), H3K36me3 is not significantly impacted by monoallelic loss of SETD2. H3K36me3-positive nuclei were reduced an average of ~20% in primary ccRCC (90% positive nuclei in uninvolved vs 70% positive nuclei in ccRCC) and reduced by ~60% in metastases (90% positive in uninvolved kidney vs 30% positive in metastases) (P<0.001). To define a kidney-specific H3K36me3 profile, we generated genome-wide H3K36me3 profiles from four cytoreductive nephrectomies and SETD2 isogenic renal cell carcinoma (RCC) cell lines using chromatin immunoprecipitation coupled with high-throughput DNA sequencing and RNA sequencing. SETD2 loss of methyltransferase activity leads to regional alterations of H3K36me3 associated with aberrant RNA splicing in a SETD2 mutant RCC and SETD2 knockout cell line. These data suggest that during progression of ccRCC, a decline in H3K36me3 is observed in distant metastases, and regional H3K36me3 alterations influence alternative splicing in ccRCC.
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Carcinoma de Células Renales/metabolismo , Histonas/metabolismo , Neoplasias Renales/metabolismo , Lisina/metabolismo , Metástasis de la Neoplasia , Carcinoma de Células Renales/patología , Inmunoprecipitación de Cromatina , Estudios de Cohortes , Histonas/química , Humanos , Neoplasias Renales/patología , MetilaciónRESUMEN
Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib-treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line 786-O was chronically treated with sunitinib and assayed for AXL, MET, epithelial-mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by short hairpin RNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets vascular endothelial growth factor receptor, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT-associated gene expression changes, including upregulation of Snail and ß-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/human umbilical vein endothelial cell co-culture models. The suppression of AXL or MET expression and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes prometastatic behavior and angiogenesis. The inhibition of AXL and MET activity may overcome resistance induced by prolonged sunitinib therapy in metastatic RCC.
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Inhibidores de la Angiogénesis/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/farmacología , Neoplasias Renales/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Pirroles/farmacología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Animales , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/patología , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Humanos , Neoplasias Renales/enzimología , Neoplasias Renales/patología , Ratones , Ratones Desnudos , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Transducción de Señal , Sunitinib , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa del Receptor AxlRESUMEN
Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor exhibiting antiangiogenic activity. Sunitinib demonstrated improved outcomes in comparison to interferon-α in a large phase III study of treatment naïve patients with metastatic renal cell carcinoma. Maintaining patients on sunitinib treatment is essential for a sustained disease control as higher exposure to sunitinib has been associated with an improved overall response rate, progression-free survival and overall survival. Various studies have compared the outcomes of patients undergoing sunitinib therapy based on modifications from their standard dose and schedule. Several studies have shown that switching to an alternate schedule with more frequent dose interruptions without affecting dose density over a 6-week cycle is associated with improved outcomes and increased tolerability.
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Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirroles/uso terapéutico , Carcinoma de Células Renales/secundario , Esquema de Medicación , Humanos , Neoplasias Renales/patología , Pronóstico , SunitinibRESUMEN
Autophagy is a conserved process involved in lysosomal degradation of protein aggregates and damaged organelles. The role of autophagy in cancer is a topic of intense debate, and the underlying mechanism is still not clear. The hypoxia-inducible factor 2α (HIF2α), an oncogenic transcription factor implicated in renal tumorigenesis, is known to be degraded by the ubiquitin-proteasome system (UPS). Here, we report that HIF2α is in part constitutively degraded by autophagy. HIF2α interacts with autophagy-lysosome system components. Inhibition of autophagy increases HIF2α, whereas induction of autophagy decreases HIF2α. The E3 ligase von Hippel-Lindau and autophagy receptor protein p62 are required for autophagic degradation of HIF2α. There is a compensatory interaction between the UPS and autophagy in HIF2α degradation. Autophagy inactivation redirects HIF2α to proteasomal degradation, whereas proteasome inhibition induces autophagy and increases the HIF2α-p62 interaction. Importantly, clear-cell renal cell carcinoma (ccRCC) is frequently associated with monoallelic loss and/or mutation of autophagy-related gene ATG7, and the low expression level of autophagy genes correlates with ccRCC progression. The protein levels of ATG7 and beclin 1 are also reduced in ccRCC tumors. This study indicates that autophagy has an anticancer role in ccRCC tumorigenesis, and suggests that constitutive autophagic degradation of HIF2α is a novel tumor suppression mechanism.
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Proteínas Adaptadoras Transductoras de Señales/genética , Autofagia/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Transformación Celular Neoplásica/genética , Neoplasias Renales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Proteína 7 Relacionada con la Autofagia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Beclina-1 , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Transformación Celular Neoplásica/patología , Células HEK293 , Humanos , Riñón , Neoplasias Renales/patología , Proteínas de la Membrana/genética , Interferencia de ARN , ARN Interferente Pequeño , Proteína Sequestosoma-1 , Enzimas Activadoras de Ubiquitina/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
Aberrant AKT activation is prevalent across multiple human cancer lineages providing an important new target for therapy. Twenty-two independent phosphorylation sites have been identified on specific AKT isoforms likely contributing to differential isoform regulation. However, the mechanisms regulating phosphorylation of individual AKT isoform molecules have not been elucidated because of the lack of robust approaches able to assess phosphorylation of multiple sites on a single AKT molecule. Using a nanofluidic proteomic immunoassay (NIA), consisting of isoelectric focusing followed by sensitive chemiluminescence detection, we demonstrate that under basal and ligand-induced conditions that the pattern of phosphorylation events is markedly different between AKT1 and AKT2. Indeed, there are at least 12 AKT1 peaks and at least 5 AKT2 peaks consistent with complex combinations of phosphorylation of different sites on individual AKT molecules. Following insulin stimulation, AKT1 was phosphorylated at Thr308 in the T-loop and Ser473 in the hydrophobic domain. In contrast, AKT2 was only phosphorylated at the equivalent sites (Thr309 and Ser474) at low levels. Further, Thr308 and Ser473 phosphorylation occurred predominantly on the same AKT1 molecules, whereas Thr309 and Ser474 were phosphorylated primarily on different AKT2 molecules. Although basal AKT2 phosphorylation was sensitive to inhibition of phosphatidylinositol 3-kinase (PI3K), basal AKT1 phosphorylation was essentially resistant. PI3K inhibition decreased pThr451 on AKT2 but not pThr450 on AKT1. Thus, NIA technology provides an ability to characterize coordinate phosphorylation of individual AKT molecules providing important information about AKT isoform-specific phosphorylation, which is required for optimal development and implementation of drugs targeting aberrant AKT activation.
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Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Línea Celular Tumoral , Proliferación Celular , Técnicas de Inactivación de Genes , Células HCT116 , Células HeLa , Humanos , Inmunoensayo , Insulina/farmacología , Focalización Isoeléctrica , Mediciones Luminiscentes , Neoplasias/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Isoformas de Proteínas/metabolismo , Proteómica/métodos , Proteínas Proto-Oncogénicas c-akt/genéticaRESUMEN
The serine/threonine kinase AKT is a key mediator of cancer cell survival. We demonstrate that transient glucose deprivation modestly induces AKT phosphorylation at both Thr308 and Ser473. In contrast, prolonged glucose deprivation induces selective AKTThr308 phosphorylation and phosphorylation of a distinct subset of AKT downstream targets leading to cell survival under metabolic stress. Glucose-deprivation-induced AKTThr308 phosphorylation is dependent on PDK1 and PI3K but not EGF receptor or IGF1R. Prolonged glucose deprivation induces the formation of a complex of AKT, PDK1 and the GRP78 chaperone protein, directing phosphorylation of AKTThr308 but not AKTSer473. Our results reveal a novel mechanism of AKT activation under prolonged glucose deprivation that protects cells from metabolic stress. The selective activation of AKTThr308 phosphorylation that occurs during prolonged nutrient deprivation may provide an unexpected opportunity for the development and implementation of drugs targeting cell metabolism and aberrant AKT signaling.
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Glucosa/deficiencia , Glucosa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Muerte Celular/fisiología , Supervivencia Celular/fisiología , Chaperón BiP del Retículo Endoplásmico , Activación Enzimática , Células HEK293 , Células HeLa , Humanos , Fosforilación , Transducción de Señal , Especificidad por SustratoRESUMEN
AIM: The multi-tyrosine kinase inhibitor pazopanib prolongs progression-free survival (PFS) versus placebo in treatment-naive and cytokine-refractory metastatic clear-cell renal cell carcinoma (ccRCC). Outcomes and safety data with pazopanib after targeted therapy (TT) are limited. METHODS: We retrospectively evaluated records of consecutive patients with metastatic ccRCC who had progressive disease (PD) after TT and received pazopanib from November 2009 through November 2011. Tumour response was assessed by a blinded radiologist using Response Evaluation Criteria In Solid Tumours (RECIST). PFS and overall survival (OS) were estimated by Kaplan-Meier methods. RESULTS: Ninety-three patients were identified. Median number of prior TTs was 2 (range, 1-5). There were 68 events (PD or death). Among 85 evaluable patients, 13 (15%) had a partial response. Median PFS was 6.5 months (95% CI: 4.5-9.7); median OS was 18.1 months (95% CI: 10.26-NA). Common adverse events (AEs) included fatigue (44%), elevated transaminases (35%), diarrhoea (30%), hypothyroidism (18%), nausea/vomiting (17%), anorexia (14%) and hypertension exacerbation (14%); 91% of AEs were grade 1/2. Eleven patients (12%) discontinued therapy due to AEs. There were no treatment-related deaths. CONCLUDING STATEMENT: Pazopanib demonstrated efficacy in patients with metastatic ccRCC after PD with other TTs. Toxicity overall was mild/moderate and manageable.
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Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Carcinoma de Células Renales/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Indazoles , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/efectos adversos , Estudios Retrospectivos , Sulfonamidas/efectos adversosRESUMEN
BACKGROUND: We investigated cytokines and angiogenic factors (CAFs) in patients with metastatic renal cell carcinoma (mRCC) treated in a randomized phase II clinical trial of sorafenib versus sorafenib+ interferon-α (IFN-α) that yielded no differences in progression-free survival (PFS). We aimed to link the CAF profile to PFS and select candidate predictive and prognostic markers for further study. METHODS: The concentrations of 52 plasma CAFs were measured pretreatment (n = 69), day 28, and day 56 using multiplex bead arrays and enzyme-linked immunosorbent assay. We investigated the association between baseline levels of CAFs with PFS and posttreatment changes. RESULTS: Unsupervised CAF clustering analysis revealed two distinct mRCC patient groups with elevated proangiogenic or proinflammatory mediators. A six-marker baseline CAF signature [osteopontin, vascular endothelial growth factor (VEGF), carbonic anhydrase 9, collagen IV, VEGF receptor-2, and tumor necrosis factor-related apoptosis-inducing ligand] correlated with PFS benefit (hazard ratio 0.20 versus 2.25, signature negative versus positive, respectively; P = 0.0002). While changes in angiogenic factors were frequently attenuated by the sorafenib+ IFN combination, most key immunomodulatory mediators increased. CONCLUSIONS: Using CAF profiling, we identified two mRCC patient groups, a candidate plasma signature for predicting PFS benefit, and distinct marker changes occurring with each treatment. This platform may provide valuable insights into renal cell carcinoma biology and the molecular consequences of targeted therapies.
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Biomarcadores de Tumor/sangre , Carcinoma de Células Renales/sangre , Citocinas/sangre , Neoplasias Renales/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Análisis por Conglomerados , Supervivencia sin Enfermedad , Ensayo de Inmunoadsorción Enzimática , Humanos , Interferón-alfa/administración & dosificación , Estimación de Kaplan-Meier , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/uso terapéutico , SorafenibRESUMEN
BACKGROUND: Von Hippel-Lindau (VHL) disease induces vascular neoplasms in multiple organs. We evaluated the safety and efficacy of sunitinib in VHL patients and examined the expression of candidate receptors in archived tissue. METHODS: Patients with VHL were given four cycles of 50 mg sunitinib daily for 28 days, followed by 14 days off. Primary end point was toxicity. Modified RECIST were used for efficacy assessment. We evaluated 20 archival renal cell carcinomas (RCCs) and 20 hemangioblastomas (HBs) for biomarker expression levels using laser-scanning cytometry (LSC). RESULTS: Fifteen patients were treated. Grade 3 toxicity included fatigue in five patients. Dose reductions were needed in 10 patients. Eighteen RCC and 21 HB lesions were evaluable. Six of the RCCs (33%) responded partially, versus none of the HBs (P = 0.014). LSC revealed that mean levels of phosphorylated vascular endothelial growth factor receptor-2 were lower in HB than in RCC endothelium (P = 0.003) and mean phosphorylated fibroblast growth factor receptor substrate-2 (pFRS2) levels were higher in HB (P = 0.003). CONCLUSIONS: Sunitinib treatment in VHL patients showed acceptable toxicity. Significant response was observed in RCC but not in HB. Greater expression of pFRS2 in HB tissue than in RCC raises the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with HB.
Asunto(s)
Antineoplásicos/uso terapéutico , Indoles/uso terapéutico , Pirroles/uso terapéutico , Enfermedad de von Hippel-Lindau/tratamiento farmacológico , Adulto , Antineoplásicos/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/metabolismo , Femenino , Hemangioblastoma/tratamiento farmacológico , Hemangioblastoma/metabolismo , Humanos , Indoles/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/metabolismo , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/tratamiento farmacológico , Proyectos Piloto , Pirroles/efectos adversos , Radiografía , Sunitinib , Resultado del Tratamiento , Adulto JovenAsunto(s)
Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Nefrectomía , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/cirugía , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/cirugía , Metástasis de la Neoplasia , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios RetrospectivosRESUMEN
BACKGROUND: Cytoreductive nephrectomy (CN) became a standard procedure in metastatic renal cell carcinoma (mRCC) in the immunotherapy era. Historically, median overall survival (OS) of patients treated with interferon alpha (IFN-α) without CN was 7.8 months. Median OS in patients treated with targeted therapy (TT) without CN is unknown. PATIENTS AND METHODS: We retrospectively reviewed records of patients with mRCC who received TT without CN. Kaplan-Meier methods and Cox regression analysis were used to estimate median OS and identify poor prognostic factors. RESULTS: One hundred and eighty-eight patients were identified. Most patients had intermediate-risk (54.8%) or poor-risk (44.1%) disease. Median OS for all patients was 10.4 months [95% confidence interval (CI) 8.1-12.5]. By multivariable analysis, elevated baseline lactate dehydrogenase and corrected calcium, performance status of two or more, retroperitoneal nodal metastasis, thrombocytosis, current smoking, two or more metastatic sites, and lymphopenia were independent risk factors for inferior OS. Patients with four or more factors had increased risk of death (hazard ratio 8.83, 95% CI 5.02-15.5, P < 0.001) and 5.5-month median OS. Nineteen patients (10.0%) survived for 2+ years. CONCLUSIONS: These data highlight the improved OS of patients with mRCC treated with TT without CN, compared with historical IFN-α treatment, and may guide the design of trials investigating the role of CN in the TT era.
Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Terapia Molecular Dirigida , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Nefrectomía , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Metastatic renal cell carcinoma (mRCC) patients treated with anti-vascular endothelial growth factor (VEGF) therapies demonstrate promising outcomes but not all patients benefit. Factors that predict response remain to be elucidated. PATIENTS AND METHODS: Nephrectomy material from 37 patients with mRCC receiving bevacizumab +/- erlotinib was used for protein and gene expression assessment. Protein lysates were subjected to reverse-phase protein array profiling. RNA extracts were used to carry out gene expression microarray-based profiling. Normalized protein and gene expression data were correlated with overall survival (OS) and progression-free survival (PFS) using univariate Cox hazard model and linear regression. Immunoblotting was carried out to validate the results. RESULTS: High protein levels of AMP-activated protein kinase and low levels of cyclin B1 (CCNB1) were associated with longer OS and PFS. Further validation revealed reduced expression and activation of phosphoinositide 3-kinase (PI3K) pathway components and cell cycle factors in patients with prolonged survival after therapy. Gene expression analysis revealed up-regulation of PI3K- and cell cycle-related pathways in patients with shorter PFS. CONCLUSIONS: The OS and PFS of bevacizumab +/- erlotinib-treated patients with renal cell carcinoma were associated with changes in expression of protein and gene expression markers related to PI3K pathway and cell cycle signaling.