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1.
Blood Cancer Discov ; 2(5): 500-517, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34568833

RESUMO

Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, ZBTB33, as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in myelodysplastic syndrome patients. Zbtb33 edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.


Assuntos
Hematopoiese Clonal , Síndromes Mielodisplásicas , Animais , Hematopoese/genética , Células-Tronco Hematopoéticas , Humanos , Camundongos , Síndromes Mielodisplásicas/genética , Splicing de RNA/genética , Fatores de Transcrição/genética
2.
Cancer Immunol Immunother ; 68(3): 407-420, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30564890

RESUMO

Therapeutic blockade of the PD-1/PD-L1 axis is recognized as an effective treatment for numerous cancer types. However, only a subset of patients respond to this treatment, warranting a greater understanding of the biological mechanisms driving immune evasion via PD-1/PD-L1 signaling and other T-cell suppressive pathways. We previously identified a head and neck squamous cell carcinoma with human papillomavirus integration in the PD-L1 locus upstream of the transmembrane domain-encoding region, suggesting expression of a truncated form of PD-L1 (Parfenov et al., Proc Natl Acad Sci USA 111(43):15544-15549, 2014). In this study, we extended this observation by performing a computational analysis of 33 other cancer types as well as human cancer cell lines, and identified additional PD-L1 isoforms with an exon 4 enrichment expressed in 20 cancers and human cancer cell lines. We demonstrate that cancer cell lines with high expression levels of exon 4-enriched PD-L1 generate a secreted form of PD-L1. Further biochemical studies of exon 4-enriched PD-L1 demonstrated that this form is secreted and maintains the capacity to bind PD-1 as well as to serve as a negative regulator on T cell function, as measured by inhibition of IL-2 and IFNg secretion. Overall, we have demonstrated that truncated forms of PD-L1 exist in numerous cancer types, and have validated that truncated PD-L1 can be secreted and negatively regulate T cell function.


Assuntos
Processamento Alternativo , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Éxons , Humanos , Interferon gama/antagonistas & inibidores , Linfocinas/farmacologia , Isoformas de Proteínas/sangue , Isoformas de Proteínas/isolamento & purificação
3.
ACS Chem Biol ; 10(12): 2687-96, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26390252

RESUMO

Despite advances in precision medicine approaches over the past decade, the majority of nonsmall cell lung cancers (NSCLCs) are refractory to treatment with targeted small molecule inhibitors. Previous work has identified mutations in the Discoidin Domain Receptor 2 (DDR2) kinase as potential therapeutic targets in NSCLCs. While DDR2 is potently targeted by several multitargeted kinase inhibitors, most notably dasatinib, toxicity has limited the clinical application of anti-DDR2 therapy. Here, we have characterized compound 1 and other tool compounds demonstrating selectivity for DDR2 and show that while these compounds inhibit DDR2 in lung cancer model systems, they display limited antiproliferative activity in DDR2 mutated cell lines as compared to dual DDR2/SRC inhibitors. We show that DDR2 and SRC are binding partners, that SRC activity is tied to DDR2 activation, and that dual inhibition of both DDR2 and SRC leads to enhanced suppression of DDR2 mutated lung cancer cell lines. These results support the further evaluation of dual SRC/DDR2 targeting in NSCLC, and we report a tool compound, compound 5, which potently inhibits both SRC and DDR2 with a distinct selectivity profile as compared to dasatinib.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Mitogênicos/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores com Domínio Discoidina , Inibidores Enzimáticos/química , Humanos , Immunoblotting , Concentração Inibidora 50 , Estrutura Molecular , Mutação , Receptores Proteína Tirosina Quinases/genética , Receptores Mitogênicos/genética
4.
Mol Cancer Ther ; 14(10): 2382-2389, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26206333

RESUMO

Genetically engineered mouse models of lung cancer have demonstrated an important role in understanding the function of novel lung cancer oncogenes and tumor-suppressor genes identified in genomic studies of human lung cancer. Furthermore, these models are important platforms for preclinical therapeutic studies. Here, we generated a mouse model of lung adenocarcinoma driven by mutation of the discoidin domain receptor 2 (DDR2) gene combined with loss of TP53. DDR2(L63V);TP53(L/L) mice developed poorly differentiated lung adenocarcinomas in all transgenic animals analyzed with a latency of 40 to 50 weeks and a median survival of 67.5 weeks. Mice expressing wild-type DDR2 with combined TP53 loss did not form lung cancers. DDR2(L63V);TP53(L/L) tumors displayed robust expression of DDR2 and immunohistochemical markers of lung adenocarcinoma comparable with previously generated models, though also displayed concomitant expression of the squamous cell markers p63 and SOX2. Tumor-derived cell lines were not solely DDR2 dependent and displayed upregulation of and partial dependence on MYCN. Combined treatment with the multitargeted DDR2 inhibitor dasatinib and BET inhibitor JQ1 inhibited tumor growth in vitro and in vivo. Together, these results suggest that DDR2 mutation can drive lung cancer initiation in vivo and provide a novel mouse model for lung cancer therapeutics studies.


Assuntos
Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Receptores Proteína Tirosina Quinases/genética , Receptores Mitogênicos/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azepinas/administração & dosagem , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Dasatinibe/administração & dosagem , Receptores com Domínio Discoidina , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Nus , Mutação de Sentido Incorreto , Proteína Proto-Oncogênica N-Myc , Proteínas Proto-Oncogênicas/metabolismo , Triazóis/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Photosynth Res ; 123(1): 45-60, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25193505

RESUMO

The ability of Prochlorococcus to numerically dominate open ocean regions and contribute significantly to global carbon cycles is dependent in large part on its effectiveness in transforming light energy into compounds used in cell growth, maintenance, and division. Integral to these processes is the carbon dioxide-concentrating mechanism (CCM), which enhances photosynthetic CO2 fixation. The CCM involves both active uptake systems that permit intracellular accumulation of inorganic carbon as the pool of bicarbonate and the system of HCO3 (-) conversion into CO2. The latter is located in the carboxysome, a microcompartment designed to promote the carboxylase activity of Rubisco. This study presents a comparative analysis of several facets of the Prochlorococcus CCM. Our analyses indicate that a core set of CCM components is shared, and their genomic organization is relatively well conserved. Moreover, certain elements, including carboxysome shell polypeptides CsoS1 and CsoS4A, exhibit striking conservation. Unexpectedly, our analyses reveal that the carbonic anhydrase (CsoSCA) and CsoS2 shell polypeptide have diversified within the lineage. Differences in csoSCA and csoS2 are consistent with a model of unequal rates of evolution rather than relaxed selection. The csoS2 and csoSCA genes form a cluster in Prochlorococcus genomes, and we identified two conserved motifs directly upstream of this cluster that differ from the motif in marine Synechococcus and could be involved in regulation of gene expression. Although several elements of the CCM remain well conserved in the Prochlorococcus lineage, the evolution of differences in specific carboxysome features could in part reflect optimization of carboxysome-associated processes in dissimilar cellular environments.


Assuntos
Dióxido de Carbono/metabolismo , Prochlorococcus/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Ciclo do Carbono , Cromossomos Bacterianos , Regulação Bacteriana da Expressão Gênica/fisiologia , Genoma Bacteriano , Dados de Sequência Molecular , Prochlorococcus/genética
6.
Mol Cancer Ther ; 13(2): 475-82, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24296828

RESUMO

The treatment of non-small cell lung cancer has evolved dramatically over the past decade with the adoption of widespread use of effective targeted therapies in patients with distinct molecular alterations. In lung squamous cell carcinoma (lung SqCC), recent studies have suggested that DDR2 mutations are a biomarker for therapeutic response to dasatinib and clinical trials are underway testing this hypothesis. Although targeted therapeutics are typically quite effective as initial therapy for patients with lung cancer, nearly all patients develop resistance with long-term exposure to targeted drugs. Here, we use DDR2-dependent lung cancer cell lines to model acquired resistance to dasatinib therapy. We perform targeted exome sequencing to identify two distinct mechanisms of acquired resistance: acquisition of the T654I gatekeeper mutation in DDR2 and loss of NF1. We show that NF1 loss activates a bypass pathway, which confers ERK dependency downstream of RAS activation. These results indicate that acquired resistance to dasatinib can occur via both second-site mutations in DDR2 and by activation of bypass pathways. These data may help to anticipate mechanisms of resistance that may be identified in upcoming clinical trials of anti-DDR2 therapy in lung cancer and suggest strategies to overcome resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Neurofibromina 1/genética , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/genética , Receptores Mitogênicos/genética , Tiazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Análise Mutacional de DNA , Dasatinibe , Receptores com Domínio Discoidina , Relação Dose-Resposta a Droga , Exoma/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Immunoblotting , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neurofibromina 1/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Mitogênicos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas ras/metabolismo
7.
Cancer Discov ; 3(12): 1355-63, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24078774

RESUMO

UNLABELLED: The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition. SIGNIFICANCE: We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non-cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Citocinas/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Evasão Tumoral , Animais , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oncogenes , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais , Microambiente Tumoral
8.
Cancer Res ; 73(16): 5195-205, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23786770

RESUMO

A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, each of which are observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small-molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. In addition, we report a patient with an FGFR2-mutated oral SCC who responded to the multitargeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SCC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Mutação , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Dimerização , Humanos , Indazóis , Interleucina-3/genética , Interleucina-3/metabolismo , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Células NIH 3T3 , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Sulfonamidas/farmacologia
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