RESUMO
Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer (PCa). Overactivated APOBEC3B, in SYNCRIP-deficient PCa cells, is a key mutator, representing the molecular source of driver mutations in some frequently mutated genes in PCa, including FOXA1, EP300. Functional screening identifies eight crucial drivers for androgen receptor (AR)-targeted therapy resistance in PCa that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR. These results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring AR-targeted therapy resistance in PCa.
Assuntos
Neoplasias da Próstata , Masculino , Humanos , Mutagênese , Mutação , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Proteínas Cromossômicas não Histona , Ribonucleoproteínas Nucleares Heterogêneas , Citidina Desaminase , Antígenos de Histocompatibilidade Menor , Complexo Repressor Polycomb 1RESUMO
Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity, the molecular mechanisms enabling the acquisition of lineage plasticity have not been fully elucidated. We reveal that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven androgen receptor (AR)-targeted therapy resistance in prostate cancer. Importantly, ectopic JAK-STAT activation is specifically required for the resistance of stem-like subclones expressing multilineage transcriptional programs but not subclones exclusively expressing the neuroendocrine-like lineage program. Both genetic and pharmaceutical inhibition of JAK-STAT signaling resensitizes resistant tumors to AR-targeted therapy. Together, these results suggest that JAK-STAT are compelling therapeutic targets for overcoming lineage plasticity-driven AR-targeted therapy resistance.
Assuntos
Janus Quinases , Neoplasias da Próstata , Humanos , Janus Quinases/genética , Masculino , Preparações Farmacêuticas , Receptores Androgênicos/genética , Fatores de Transcrição STAT/genéticaRESUMO
Metastasis is the principal cause of cancer related deaths. Tumor invasion is essential for metastatic spread. However, determinants of invasion are poorly understood. We addressed this knowledge gap by leveraging a unique attribute of kidney cancer. Renal tumors invade into large vessels forming tumor thrombi (TT) that migrate extending sometimes into the heart. Over a decade, we prospectively enrolled 83 ethnically-diverse patients undergoing surgical resection for grossly invasive tumors at UT Southwestern Kidney Cancer Program. In this study, we perform comprehensive histological analyses, integrate multi-region genomic studies, generate in vivo models, and execute functional studies to define tumor invasion and metastatic competence. We find that invasion is not always associated with the most aggressive clone. Driven by immediate early genes, invasion appears to be an opportunistic trait attained by subclones with diverse oncogenomic status in geospatial proximity to vasculature. We show that not all invasive tumors metastasize and identify determinants of metastatic competency. TT associated with metastases are characterized by higher grade, mTOR activation and a particular immune contexture. Moreover, TT grade is a better predictor of metastasis than overall tumor grade, which may have implications for clinical practice.
Assuntos
Carcinoma de Células Renais/secundário , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/patologia , Trombose/genética , Idoso , Animais , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Feminino , Humanos , Rim/irrigação sanguínea , Rim/patologia , Neoplasias Renais/complicações , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Estudos Prospectivos , RNA-Seq , Fatores de Risco , Trombose/patologia , Sequenciamento do Exoma , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Renal cell carcinoma (RCC) is characterized by a particularly broad metastatic swath, and, enigmatically, when the pancreas is a destination, the disease is associated with improved survival. Intrigued by this observation, we sought to characterize the clinical behavior, therapeutic implications, and underlying biology. While pancreatic metastases (PM) are infrequent, we identified 31 patients across 2 institutional cohorts and show that improved survival is independent of established prognostic variables, that these tumors are exquisitely sensitive to antiangiogenic agents and resistant to immune checkpoint inhibitors (ICIs), and that they are characterized by a distinctive biology. Primary tumors of patients with PM exhibited frequent PBRM1 mutations, 3p loss, and 5q amplification, along with a lower frequency of aggressive features such as BAP1 mutations and loss of 9p, 14q, and 4q. Gene expression analyses revealed constrained evolution with remarkable uniformity, reduced effector T cell gene signatures, and increased angiogenesis. Similar findings were observed histopathologically. Thus, RCC metastatic to the pancreas is characterized by indolent biology, heightened angiogenesis, and an uninflamed stroma, likely underlying its good prognosis, sensitivity to antiangiogenic therapies, and refractoriness to ICI. These data suggest that metastatic organotropism may be an indicator of a particular biology with prognostic and treatment implications for patients.
Assuntos
Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Cromossomos Humanos/genética , Cromossomos Humanos/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Metástase Neoplásica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/secundário , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Lack of responsiveness to checkpoint inhibitors is a central problem in the modern era of cancer immunotherapy. Tumor neoantigens are critical targets of the host antitumor immune response, and their presence correlates with the efficacy of immunotherapy treatment. Many studies involving assessment of tumor neoantigens principally focus on total neoantigen load, which simplistically treats all neoantigens equally. Neoantigen load has been linked with treatment response and prognosis in some studies but not others. We developed a Cauchy-Schwarz index of Neoantigens (CSiN) score to better account for the degree of concentration of immunogenic neoantigens in truncal mutations. Unlike total neoantigen load determinations, CSiN incorporates the effect of both clonality and MHC binding affinity of neoantigens when characterizing tumor neoantigen profiles. By analyzing the clinical responses in 501 treated patients with cancer (with most receiving checkpoint inhibitors) and the overall survival of 1978 patients with cancer at baseline, we showed that CSiN scores predict treatment response to checkpoint inhibitors and prognosis in patients with melanoma, lung cancer, and kidney cancer. CSiN score substantially outperformed prior genetics-based prediction methods of responsiveness and fills an important gap in research involving assessment of tumor neoantigen burden.
Assuntos
Antígenos de Neoplasias/imunologia , Células Clonais/imunologia , Células Clonais/patologia , Imunoterapia , Neoplasias/patologia , Neoplasias/terapia , Idoso , Antígenos de Neoplasias/genética , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Melanoma/diagnóstico , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Mutação , Neoplasias/imunologia , Resultado do TratamentoRESUMO
PURPOSE: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1ß, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients. PATIENTS AND METHODS: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies. RESULTS: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance. CONCLUSIONS: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Indanos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Sulfonas/uso terapêutico , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Ensaios Clínicos Fase I como Assunto , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética Multiparamétrica/métodos , Estudos ProspectivosRESUMO
By leveraging tumorgraft (patient-derived xenograft) RNA-sequencing data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in renal cell carcinoma (RCC) and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology, and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for regulatory T cells, natural killer cells, TH1 cells, neutrophils, macrophages, B cells, and CD8+ T cells. IS is enriched for aggressive RCCs, including BAP1-deficient clear-cell and type 2 papillary tumors. The IS subtype correlated with systemic manifestations of inflammation such as thrombocytosis and anemia, which are enigmatic predictors of poor prognosis. Furthermore, IS was a strong predictor of poor survival. Our analyses suggest that tumor cells drive the stromal immune response. These data provide a missing link between tumor cells, the TME, and systemic factors.Significance: We undertook a novel empirical approach to dissect the renal cell carcinoma TME by leveraging tumorgrafts. The dissection and downstream analyses uncovered missing links between tumor cells, the TME, systemic manifestations of inflammation, and poor prognosis. Cancer Discov; 8(9); 1142-55. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047.
Assuntos
Carcinoma de Células Renais/patologia , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Inflamação/genética , Neoplasias Renais/patologia , Animais , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/genética , Análise por Conglomerados , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Inflamação/patologia , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Camundongos , Transplante de Neoplasias , Prognóstico , Análise de Sequência de RNA/métodos , Análise de Sobrevida , Microambiente Tumoral , Aprendizado de Máquina não Supervisionado , Sequenciamento do Exoma/métodosRESUMO
Oncogenes are genes that have the potential to cause cancer. Oncogene research can provide insight into the occurrence and development of cancer, thereby helping to prevent cancer and to design effective treatments. This study proposes a network method called the oncogene prediction method based on shortest path algorithm (OPMSP) for the identification of novel oncogenes in a large protein network built using protein-protein interaction data. Novel putative genes were extracted from the shortest paths connecting any two known oncogenes. Then, they were filtered by a randomization test, and the linkages among them and known oncogenes were measured by protein interaction and sequence data. Thirty-seven new putative oncogenes were identified by this method. The enrichment analysis of the 37 putative oncogenes indicated that they are highly associated with several biological processes related to the initiation, progression and metastasis of tumors. Six of these genes-ESR1, CDK9, SEPT2, HOXA10, LMX1B, and NR2C2-are extensively discussed. Several lines of evidence indicate that they may be novel oncogenes.
Assuntos
Biologia Computacional/métodos , Neoplasias/genética , Oncogenes/genética , Mapas de Interação de Proteínas/genética , Algoritmos , Sequência de Aminoácidos , Quinase 9 Dependente de Ciclina/genética , Receptor alfa de Estrogênio/genética , Proteínas Homeobox A10 , Proteínas de Homeodomínio/genética , Proteínas com Homeodomínio LIM/genética , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Septinas/genética , Fatores de Transcrição/genéticaRESUMO
Mutations in the G-protein-coupled receptor PROKR2 have been identified in patients with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) manifesting with delayed puberty and infertility. Recently, the homozygous mutation V274D was identified in a man displaying KS with an apparent reversal of hypogonadism. The affected amino acid, valine 274, is located at the junction region of the third intracellular loop (IL3) and the sixth transmembrane domain (TM6). In this study, we first studied the effect of V274D and related mutations (V274A, V274T, and V274R) on the signaling activity and cell surface expression of PROKR2. Our data indicate that a charged amino acid substitution at residue 274 of PROKR2 results in low cell surface expression and loss-of-function. Furthermore, we studied the effects of two clusters of basic amino acids located at the proximal region of Val274 on the cell surface expression and function of PROKR2. The deletion of RRK (270-272) resulted in undetectable cell surface expression, whereas RKR (264-266)-deleted PROKR2 was expressed normally on the cell surface but showed loss-of-function due to a deficiency in G-protein coupling. Our data indicate that the distal region of the IL3 of PROKR2 may differentially influence receptor trafficking and G-protein coupling.
Assuntos
Receptores Acoplados a Proteínas G/química , Receptores de Peptídeos/química , Motivos de Aminoácidos , Substituição de Aminoácidos , Membrana Celular/metabolismo , Deleção de Genes , Células HEK293 , Humanos , Hipogonadismo/genética , Síndrome de Kallmann/genética , Modelos Moleculares , Mutação , Sinais Direcionadores de Proteínas , Estrutura Terciária de Proteína , Transporte Proteico , Receptores Acoplados a Proteínas G/fisiologia , Receptores de Peptídeos/fisiologia , Transdução de Sinais , Valina/químicaRESUMO
TACI is a member of the tumor necrosis factor receptor superfamily and serves as a key regulator of B cell function. The extracellular domain of a typical TNFR contains multiple copies of CRD, which bind in the monomermonomer interfaces of a trimeric ligand. TACI binds to two ligands, APRIL and BAFF, with high affinity and contains two CRD in its extracellular regions, while BCMA and BR3, contain a single or partial CRD for binding the two ligands. However, TACI can be classified as a single CRD receptor because the amino-terminal CRD1 doesn't contribute to ligand binding. To obtain a new variant of TACI possessing higher affinities for binding, we fused a repeat sequence of CRD2 to the N-terminus of the short form of TACI. The new APRIL antagonist peptide, CRD2-shortTACI-Fc, was designed based on the modeling 3-D complex structure of TACI and APRIL. As expected, the purified recombinant CRD2-shortTACI-Fc fusion protein could bind to APRIL in vitro and demonstrated dose-dependent inhibition of APRIL-induced proliferative activity in Raji cells. We found that CRD2-shortTACI-Fc, has a higher affinity for binding to ligands than short-TACI-Fc, which contains a single CRD2.