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1.
Sci Transl Med ; 13(581)2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597266

RESUMO

Although immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein-1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes. Moreover, expansion of peripheral blood CD8+ T cell populations specific for melanocyte antigens was observed only in patients who responded to anti-PD-1 therapy, suggesting that ICI can promote breakdown of tolerance toward tumor-lineage self-antigens. In a mouse model of poorly immunogenic melanomas, spreading of epitope recognition toward wild-type melanocyte antigens was associated with markedly improved anti-PD-1 efficacy in two independent approaches: introduction of neoantigens by ultraviolet (UV) B radiation mutagenesis or the therapeutic combination of ablative fractional photothermolysis plus imiquimod. Complete responses against UV mutation-bearing tumors after anti-PD-1 resulted in protection from subsequent engraftment of melanomas lacking any shared neoantigens, as well as pancreatic adenocarcinomas forcibly overexpressing melanocyte-lineage antigens. Our data demonstrate that somatic mutations are sufficient to provoke strong antitumor responses after checkpoint blockade, but long-term responses are not restricted to these putative neoantigens. Epitope spreading toward T cell recognition of wild-type tumor-lineage self-antigens represents a common pathway for successful response to ICI, which can be evoked in neoantigen-deficient tumors by combination therapy with ablative fractional photothermolysis and imiquimod.

2.
Nat Commun ; 11(1): 3644, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686686

RESUMO

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Neoplasias/genética , Neoplasias do Colo/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Mutação , Prognóstico , Proteína Supressora de Tumor p53/genética
3.
Nat Med ; 26(8): 1271-1279, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32572264

RESUMO

Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis1. To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We found that the previously described immunoreactive and mesenchymal subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells2. Malignant cell variability was partly explained by heterogeneous copy number alteration patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in single-cell RNA sequencing of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient ascites-derived xenograft models. Inhibition of the JAK/STAT pathway, which was expressed in both malignant cells and cancer-associated fibroblasts, had potent anti-tumor activity in primary short-term cultures and patient-derived xenograft models. Our work contributes to resolving the HSGOC landscape3-5 and provides a resource for the development of novel therapeutic approaches.


Assuntos
Ascite/genética , Cistadenoma Seroso/genética , Neoplasias Ovarianas/genética , Análise de Célula Única , Ascite/patologia , Linhagem Celular Tumoral , Cistadenoma Seroso/patologia , Variações do Número de Cópias de DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Janus Quinase 1/genética , Gradação de Tumores , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/patologia , Prognóstico , Fatores de Transcrição STAT/genética , Análise de Sequência de RNA , Transdução de Sinais/genética
4.
Cancer Discov ; 10(8): 1174-1193, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32404308

RESUMO

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in AKT1, RAS, and AURKA-have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ metastatic breast cancer.This article is highlighted in the In This Issue feature, p. 1079.

5.
Cell ; 180(2): 387-402.e16, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31978347

RESUMO

Proteins are essential agents of biological processes. To date, large-scale profiling of cell line collections including the Cancer Cell Line Encyclopedia (CCLE) has focused primarily on genetic information whereas deep interrogation of the proteome has remained out of reach. Here, we expand the CCLE through quantitative profiling of thousands of proteins by mass spectrometry across 375 cell lines from diverse lineages to reveal information undiscovered by DNA and RNA methods. We observe unexpected correlations within and between pathways that are largely absent from RNA. An analysis of microsatellite instable (MSI) cell lines reveals the dysregulation of specific protein complexes associated with surveillance of mutation and translation. These and other protein complexes were associated with sensitivity to knockdown of several different genes. These data in conjunction with the wider CCLE are a broad resource to explore cellular behavior and facilitate cancer research.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Neoplasias/metabolismo , Proteoma/metabolismo , Linhagem Celular Tumoral , Perfilação da Expressão Gênica/métodos , Humanos , Espectrometria de Massas/métodos , Instabilidade de Microssatélites , Mutação/genética , Proteômica/métodos
6.
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
7.
Nat Commun ; 10(1): 4346, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554815

RESUMO

Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase   (IDO/TDO) inhibitors.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Everolimo/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Melanoma/tratamento farmacológico , Metabolômica , Nivolumabe/uso terapêutico , Adaptação Fisiológica/efeitos dos fármacos , Idoso , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/metabolismo , Ensaios Clínicos como Assunto , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/sangue , Neoplasias Renais/metabolismo , Cinurenina/sangue , Masculino , Melanoma/sangue , Melanoma/metabolismo , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Resultado do Tratamento , Triptofano/sangue
8.
Mol Cancer Res ; 17(11): 2281-2293, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31462500

RESUMO

High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function and loss-of-function screens. In an open reading frame overexpression screen, followed by a mini-pool secondary screen, anti-apoptotic genes including BCL2L1 (BCL-XL) and BCL2L2 (BCL-W) were associated with chemotherapy resistance. In a CRISPR-Cas9 knockout screen, loss of BCL2L1 decreased cell survival whereas loss of proapoptotic genes promoted resistance. To dissect the role of individual anti-apoptotic proteins in HGSOC chemotherapy response, we evaluated overexpression or inhibition of BCL-2, BCL-XL, BCL-W, and MCL1 in HGSOC cell lines. Overexpression of anti-apoptotic proteins decreased apoptosis and modestly increased cell viability upon cisplatin or paclitaxel treatment. Conversely, specific inhibitors of BCL-XL, MCL1, or BCL-XL/BCL-2, but not BCL-2 alone, enhanced cell death when combined with cisplatin or paclitaxel. Anti-apoptotic protein inhibitors also sensitized HGSOC cells to the poly (ADP-ribose) polymerase inhibitor olaparib. These unbiased screens highlight anti-apoptotic proteins as mediators of chemotherapy resistance in HGSOC, and support inhibition of BCL-XL and MCL1, alone or combined with chemotherapy or targeted agents, in treatment of primary and recurrent HGSOC. IMPLICATIONS: Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/genética , Apoptose/genética , Resistencia a Medicamentos Antineoplásicos , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Neoplasias Ovarianas/genética , Proteína bcl-X/antagonistas & inibidores , Linhagem Celular Tumoral , Cisplatino/farmacologia , Feminino , Genômica , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
9.
Clin Cancer Res ; 25(16): 5135-5142, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31164371

RESUMO

PURPOSE: Leiomyosarcoma and liposarcoma are common subtypes of soft tissue sarcoma (STS). Patients with metastatic leiomyosarcoma or dedifferentiated liposarcoma (DDLPS) typically have worse outcomes compared with localized leiomyosarcoma or well-differentiated liposarcoma (WDLPS). A better understanding of genetic changes between primary/metastatic leiomyosarcoma and between WDLPS/DDLPS may provide insight into their genetic evolution. EXPERIMENTAL DESIGN: We interrogated whole-exome sequencing (WES) from "trios" of normal tissue, primary tumor, and metastatic tumor from individual patients with leiomyosarcoma (n = 9), and trios of normal tissue, well-differentiated tumor, and dedifferentiated tumor from individual patients with liposarcoma (n = 19). Specifically, we performed mutational, copy number, and tumor evolution analyses on these cohorts and compared patterns among leiomyosarcoma and liposarcoma trios. RESULTS: Leiomyosarcoma cases harbored shared drivers through a typical parent/child relationship where the metastatic tumor was derived from the primary tumor. In contrast, while all liposarcoma cases shared the characteristic focal chromosome 12 amplicon, most paired liposarcoma cases did not share additional mutations, suggesting a divergent evolutionary pattern from a common precursor. No highly recurrent genomic alterations from WES were identified that could be implicated as driving the progression of disease in either sarcoma subtype. CONCLUSIONS: From a genomic perspective, leiomyosarcoma metastases contain genetic alterations that are also found in primary tumors. WDLPS and DDLPS, however, appear to divergently evolve from a common precursor harboring 12q amplification, rather than as a transformation to a higher-grade tumor. Further efforts to identify specific drivers of these distinct evolutionary patterns may inform future translational and clinical research in STS.


Assuntos
Transformação Celular Neoplásica/genética , Predisposição Genética para Doença , Genômica , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Lipossarcoma/genética , Lipossarcoma/patologia , Adulto , Idoso , Biópsia , Feminino , Perfilação da Expressão Gênica , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Estudos Retrospectivos , Sequenciamento Completo do Exoma
11.
Cell Chem Biol ; 26(9): 1306-1314.e5, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31204288

RESUMO

The proteinaceous extracellular matrix (ECM) is vital for the survival, proliferation, migration, and differentiation of many types of cancer. However, little is known regarding metabolic pathways required for ECM secretion. By using an unbiased computational approach, we searched for enzymes whose suppression may lead to disruptions in protein secretion. Here, we show that 6-phosphogluconate dehydrogenase (PGD), a cytosolic enzyme involved in carbohydrate metabolism, is required for ER structural integrity and protein secretion. Chemical inhibition or genetic suppression of PGD activity led to cell stress accompanied by significantly expanded ER volume and was rescued by compensating endogenous glutathione supplies. Our results also suggest that this characteristic ER-dilation phenotype may be a general marker indicating increased ECM protein congestion inside cells and decreased secretion. Thus, PGD serves as a link between cytosolic carbohydrate metabolism and protein secretion.


Assuntos
Metabolismo dos Carboidratos/fisiologia , Glutationa/metabolismo , Fosfogluconato Desidrogenase/metabolismo , Sistemas de Translocação de Proteínas/metabolismo , Linhagem Celular Tumoral , Citosol/metabolismo , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Matriz Extracelular/metabolismo , Humanos , Fosfogluconato Desidrogenase/fisiologia , Sistemas de Translocação de Proteínas/fisiologia
12.
Nat Med ; 25(5): 850-860, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31068703

RESUMO

Despite considerable efforts to identify cancer metabolic alterations that might unveil druggable vulnerabilities, systematic characterizations of metabolism as it relates to functional genomic features and associated dependencies remain uncommon. To further understand the metabolic diversity of cancer, we profiled 225 metabolites in 928 cell lines from more than 20 cancer types in the Cancer Cell Line Encyclopedia (CCLE) using liquid chromatography-mass spectrometry (LC-MS). This resource enables unbiased association analysis linking the cancer metabolome to genetic alterations, epigenetic features and gene dependencies. Additionally, by screening barcoded cell lines, we demonstrated that aberrant ASNS hypermethylation sensitizes subsets of gastric and hepatic cancers to asparaginase therapy. Finally, our analysis revealed distinct synthesis and secretion patterns of kynurenine, an immune-suppressive metabolite, in model cancer cell lines. Together, these findings and related methodology provide comprehensive resources that will help clarify the landscape of cancer metabolism.


Assuntos
Neoplasias/metabolismo , Animais , Asparaginase/uso terapêutico , Asparagina/metabolismo , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/antagonistas & inibidores , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/metabolismo , Linhagem Celular Tumoral , Metilação de DNA , Feminino , Técnicas de Silenciamento de Genes , Humanos , Cinurenina/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Metaboloma , Camundongos , Camundongos Nus , Neoplasias/genética , Neoplasias/terapia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/terapia
13.
Cancer Res ; 79(9): 2352-2366, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30819666

RESUMO

Combinatorial inhibition of MEK1/2 and CDK4/6 is currently undergoing clinical investigation in NRAS-mutant melanoma. To prospectively map the landscape of resistance to this investigational regimen, we utilized a series of gain- and loss-of-function forward genetic screens to identify modulators of resistance to clinical inhibitors of MEK1/2 and CDK4/6 alone and in combination. First, we identified NRAS-mutant melanoma cell lines that were dependent on NRAS for proliferation and sensitive to MEK1/2 and CDK4/6 combination treatment. We then used a genome-scale ORF overexpression screen and a CRISPR knockout screen to identify modulators of resistance to each inhibitor alone or in combination. These orthogonal screening approaches revealed concordant means of achieving resistance to this therapeutic modality, including tyrosine kinases, RAF, RAS, AKT, and PI3K signaling. Activated KRAS was sufficient to cause resistance to combined MEK/CDK inhibition and to replace genetic depletion of oncogenic NRAS. In summary, our comprehensive functional genetic screening approach revealed modulation of resistance to the inhibition of MEK1/2, CDK4/6, or their combination in NRAS-mutant melanoma. SIGNIFICANCE: These findings reveal that NRAS-mutant melanomas can acquire resistance to genetic ablation of NRAS or combination MEK1/2 and CDK4/6 inhibition by upregulating activity of the RTK-RAS-RAF and RTK-PI3K-AKT signaling cascade.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , GTP Fosfo-Hidrolases/genética , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , Melanoma/tratamento farmacológico , Proteínas de Membrana/genética , Mutação , Antineoplásicos/farmacologia , Apoptose , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Humanos , Melanoma/genética , Melanoma/patologia , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
14.
Cancer Discov ; 9(4): 526-545, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30709805

RESUMO

Although the majority of BRAF-mutant melanomas respond to BRAF/MEK inhibitors, these agents are not typically curative. Moreover, they are largely ineffective in NRAS- and NF1-mutant tumors. Here we report that genetic and chemical suppression of HDAC3 potently cooperates with MAPK pathway inhibitors in all three RAS pathway-driven tumors. Specifically, we show that entinostat dramatically enhances tumor regression when combined with BRAF/MEK inhibitors, in both models that are sensitive or relatively resistant to these agents. Interestingly, MGMT expression predicts responsiveness and marks tumors with latent defects in DNA repair. BRAF/MEK inhibitors enhance these defects by suppressing homologous recombination genes, inducing a BRCA-like state; however, addition of entinostat triggers the concomitant suppression of nonhomologous end-joining genes, resulting in a chemical synthetic lethality caused by excessive DNA damage. Together, these studies identify melanomas with latent DNA repair defects, describe a promising drug combination that capitalizes on these defects, and reveal a tractable therapeutic biomarker. SIGNIFICANCE: BRAF/MEK inhibitors are not typically curative in BRAF-mutant melanomas and are ineffective in NRAS- and NF1-mutant tumors. We show that HDAC inhibitors dramatically enhance the efficacy of BRAF/MEK inhibitors in sensitive and insensitive RAS pathway-driven melanomas by coordinately suppressing two DNA repair pathways, and identify a clinical biomarker that predicts responsiveness.See related commentary by Lombard et al., p. 469.This article is highlighted in the In This Issue feature, p. 453.


Assuntos
Reparo do DNA/genética , Genes ras/genética , MAP Quinase Quinase Quinases/genética , Melanoma/genética , Humanos , Proteínas Proto-Oncogênicas B-raf
15.
Cell ; 175(4): 984-997.e24, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388455

RESUMO

Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.


Assuntos
Antineoplásicos/uso terapêutico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Melanoma/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Linfócitos T/imunologia , Evasão Tumoral , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Imunoterapia/métodos , Masculino , Melanoma/tratamento farmacológico , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia
16.
Mol Genet Genomic Med ; 6(6): 898-909, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30133189

RESUMO

BACKGROUND: Clinical genome and exome sequencing (CGES) is primarily used to address specific clinical concerns by detecting risk of future disease, clarifying diagnosis, or directing treatment. Additionally, CGES makes possible the disclosure of autosomal recessive and X-linked carrier results as additional secondary findings, and research about the impact of carrier results disclosure in this context is needed. METHODS: Representatives from 11 projects in the clinical sequencing exploratory research (CSER) consortium collected data from their projects using a structured survey. The survey focused on project characteristics, which variants were offered and/or disclosed to participants as carrier results, methods for carrier results disclosure, and project-specific outcomes. We recorded quantitative responses and report descriptive statistics with the aim of describing the variability in approaches to disclosing carrier results in translational genomics research projects. RESULTS: The proportion of participants with carrier results was related to the number of genes included, ranging from 3% (three genes) to 92% (4,600 genes). Between one and seven results were disclosed to those participants who received any positive result. Most projects offered participants choices about whether to receive some or all of the carrier results. There were a range of approaches to communicate results, and many projects used separate approaches for disclosing positive and negative results. CONCLUSION: Future translational genomics research projects will need to make decisions regarding whether and how to disclose carrier results. The CSER consortium experience identifies approaches that balance potential participant interest while limiting impact on project resources.


Assuntos
Revelação , Triagem de Portadores Genéticos/métodos , Aconselhamento Genético/métodos , Utilização de Instalações e Serviços , Triagem de Portadores Genéticos/estatística & dados numéricos , Aconselhamento Genético/estatística & dados numéricos , Humanos , Pesquisa Médica Translacional/métodos , Sequenciamento Completo do Genoma/métodos
17.
Mol Cell ; 71(4): 554-566.e7, 2018 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-30078722

RESUMO

Chromosomal rearrangements resulting in the fusion of TMPRSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers. However, the mechanism by which ERG promotes oncogenic gene expression and proliferation remains incompletely understood. Here, we identify a binding interaction between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which is conserved among other oncogenic ETS factors, including ETV1, ETV4, and ETV5. We find that ERG drives genome-wide retargeting of BAF complexes in a manner dependent on binding of ERG to the ETS DNA motif. Moreover, ERG requires intact BAF complexes for chromatin occupancy and BAF complex ATPase activity for target gene regulation. In a prostate organoid model, BAF complexes are required for ERG-mediated basal-to-luminal transition, a hallmark of ERG activity in prostate cancer. These observations suggest a fundamental interdependence between ETS transcription factors and BAF chromatin remodeling complexes in cancer.


Assuntos
Carcinogênese/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/genética , Serina Endopeptidases/genética , Proteínas E1A de Adenovirus/genética , Proteínas E1A de Adenovirus/metabolismo , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células , Cromatina/química , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , DNA/genética , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Organoides/metabolismo , Organoides/patologia , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ligação Proteica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-ets , Serina Endopeptidases/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo
18.
Cancer Discov ; 8(9): 1096-1111, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29903880

RESUMO

Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC.Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096-111. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.


Assuntos
Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica/métodos , Variação Genética , Genômica/métodos , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/tratamento farmacológico , Reparo do DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Mutação em Linhagem Germinativa , Recombinação Homóloga , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Medicina de Precisão , Análise de Sequência de RNA/métodos , Sequenciamento Completo do Exoma/métodos
19.
Oncoimmunology ; 7(7): e1442999, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29900052

RESUMO

Inhibitors targeting the PDCD1 (programmed cell death 1, PD-1) immune checkpoint pathway have revolutionized cancer treatment strategies. The TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PDCD1 ligand 1, PD-L1) expression and tumor-infiltrating lymphocytes (TIL) has been proposed to predict response to immunotherapy. It remains to be determined clinical, pathological, and molecular features of TIME subtypes of colorectal cancer. Using 812 colon and rectal carcinoma cases from the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association of tumor characteristics and survival outcomes with four TIME subtypes (TIME 1, CD274low/TILabsent; TIME 2, CD274high/TILpresent; TIME 3, CD274low/TILpresent; and TIME 4, CD274high/TILabsent). In survival analyses, Cox proportional hazards models were adjusted for potential confounders, including microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, LINE-1 methylation level, and KRAS, BRAF, and PIK3CA mutation status. TIME subtypes 1, 2, 3 and 4 had 218 (27%), 117 (14%), 103 (13%), and 374 (46%) colorectal cancer cases, respectively. Compared with TIL-absent subtypes (TIME 1 and 4), TIL-present subtypes (TIME 2 and 3) were associated with high-level MSI, high-degree CIMP, BRAF mutation, and higher amounts of neoantigens (p < 0.001). TIME subtypes were not significantly associated with colorectal cancer-specific or overall survival. In conclusion, TIL-present TIME subtypes of colorectal cancer are associated with high levels of MSI and neoantigen load, supporting better responsiveness to cancer immunotherapy. Further studies examining tumor molecular alterations and additional factors in the tumor microenvironment may inform development of immunoprevention and immunotherapy strategies.

20.
Cancer Cell ; 33(5): 801-815, 2018 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-29763622

RESUMO

Despite advances in cancer biology and therapeutics, drug resistance remains problematic. Resistance is often multifactorial, heterogeneous, and prone to undersampling. Nonetheless, many individual mechanisms of targeted therapy resistance may coalesce into a smaller number of convergences, including pathway reactivation (downstream re-engagement of original effectors), pathway bypass (recruitment of a parallel pathway converging on the same downstream output), and pathway indifference (development of a cellular state independent of the initial therapeutic target). Similar convergences may also underpin immunotherapy resistance. Such parsimonious, convergence-based frameworks may help explain resistance across tumor types and therapeutic categories and may also suggest strategies to overcome it.


Assuntos
Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias/metabolismo , Humanos , Imunoterapia , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Medicina de Precisão
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