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1.
Mol Cancer Res ; 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38747975

RESUMO

Small-cell lung cancer (SCLC) accounts for nearly 15% of all lung cancers. Although patients respond to first-line therapy readily, rapid relapse is inevitable, with few treatment options in the second-line setting. Here, we describe SCLC cell lines harboring amplification of MYC and MYCN, but not MYCL1 nor non-amplified MYC cell lines, exhibit superior sensitivity to treatment with the pan-BET bromodomain protein inhibitor Mivebresib (ABBV-075). Silencing MYC and MYCN partially rescued SCLC cell lines harboring these respective amplifications from the anti-proliferative effects of mivebresib. Further characterization of genome-wide binding of MYC, MYCN, and MYCL1 uncovered unique enhancer and epigenetic preferences. Implications: Our study suggests that chromatin landscapes could establish cell states with unique gene expression programs, conveying sensitivity to epigenetic inhibitors such as mivebresib.

2.
Mol Cancer Ther ; 23(7): 949-960, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38507740

RESUMO

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.


Assuntos
Sinergismo Farmacológico , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas Proto-Oncogênicas c-bcl-2 , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Humanos , Animais , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Linhagem Celular Tumoral , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Modelos Animais de Doenças
3.
Mol Cancer Ther ; 20(10): 1809-1819, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34253595

RESUMO

Dual bromodomain BET inhibitors that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4, and BRDT have displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of gastrointestinal toxicity, have presented as dose-limiting adverse events that may have prevented escalation to higher dose levels required for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain of the four BET family proteins. In contrast to the broad antiproliferative activities observed with dual bromodomain BET inhibitors, ABBV-744 displayed significant antiproliferative activities largely although not exclusively in cancer cell lines derived from acute myeloid leukemia and androgen receptor positive prostate cancer. Studies in acute myeloid leukemia xenograft models demonstrated antitumor efficacy for ABBV-744 that was comparable with the pan-BET inhibitor ABBV-075 but with an improved therapeutic index. Enhanced antitumor efficacy was also observed with the combination of ABBV-744 and the BCL-2 inhibitor, venetoclax compared with monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Piridinas/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose , Proliferação de Células , Quimioterapia Combinada , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
5.
NAR Cancer ; 3(1): zcaa046, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33554122

RESUMO

The TMPRSS2-ERG gene fusion and subsequent overexpression of the ERG transcription factor occurs in ∼50% of prostate tumors, making it the most common abnormality of the prostate cancer genome. While ERG has been shown to drive tumor progression and cancer-related phenotypes, as a transcription factor it is difficult to target therapeutically. Using a genetic screen, we identified the toll-like receptor 4 (TLR4) signaling pathway as important for ERG function in prostate cells. Our data confirm previous reports that ERG can transcriptionally activate TLR4 gene expression; however, using a constitutively active ERG mutant, we demonstrate that the critical function of TLR4 signaling is upstream, promoting ERG phosphorylation at serine 96 and ERG transcriptional activation. The TLR4 inhibitor, TAK-242, attenuated ERG-mediated migration, clonogenic survival, target gene activation and tumor growth. Together these data indicate a mechanistic basis for inhibition of TLR4 signaling as a treatment for ERG-positive prostate cancer.

6.
Nature ; 578(7794): 306-310, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31969702

RESUMO

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/química , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Domínios Proteicos/efeitos dos fármacos , Piridinas/farmacologia , Pirróis/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/química , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Elementos Facilitadores Genéticos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Piridinas/efeitos adversos , Piridinas/toxicidade , Pirróis/efeitos adversos , Pirróis/toxicidade , Ratos , Receptores Androgênicos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cancer Lett ; 414: 190-204, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29174800

RESUMO

Metastatic colonization involves paracrine/juxtacrine interactions with the microenvironment inducing an adaptive response through transcriptional regulation. However, the identities of transcription factors (TFs) induced by the metastatic microenvironment in ovarian cancer (OC) and their mechanism of action is poorly understood. Using an organotypic 3D culture model recapitulating the early events of metastasis, we identified ETS1 as the most upregulated member of the ETS family of TFs in metastasizing OC cells as they interacted with the microenvironment. ETS1 was regulated by p44/42 MAP kinase signaling activated in the OC cells interacting with mesothelial cells at the metastatic site. Human OC tumors had increased expression of ETS1, which predicted poor prognosis. ETS1 regulated OC metastasis both in vitro and in mouse xenografts. A combination of ChIP-seq and RNA-seq analysis and functional rescue experiments revealed FAK as the key transcriptional target and downstream effector of ETS1. Taken together, our results indicate that ETS1 is an essential transcription factor induced in OC cells by the microenvironment, which promotes metastatic colonization though the transcriptional upregulation of its target FAK.


Assuntos
Quinase 1 de Adesão Focal/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/genética , Proteína Proto-Oncogênica c-ets-1/genética , Microambiente Tumoral/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Quinase 1 de Adesão Focal/metabolismo , Humanos , Estimativa de Kaplan-Meier , Camundongos Nus , Metástase Neoplásica , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteína Proto-Oncogênica c-ets-1/metabolismo , Interferência de RNA , Transplante Heterólogo
8.
Nucleic Acids Res ; 45(8): 4452-4462, 2017 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-28119415

RESUMO

Aberrant activation of RAS/MAPK signaling is a driver of over one third of all human carcinomas. The homologous transcription factors ETS1 and ETS2 mediate activation of gene expression programs downstream of RAS/MAPK signaling. ETS1 is important for oncogenesis in many tumor types. However, ETS2 can act as an oncogene in some cellular backgrounds, and as a tumor suppressor in others, and the molecular mechanism responsible for this cell-type specific function remains unknown. Here, we show that ETS1 and ETS2 can regulate a cell migration gene expression program in opposite directions, and provide the first comparison of the ETS1 and ETS2 cistromes. This genomic data and an ETS1 deletion line reveal that the opposite function of ETS2 is a result of binding site competition and transcriptional attenuation due to weaker transcriptional activation by ETS2 compared to ETS1. This weaker activation was mapped to the ETS2 N-terminus and a specific interaction with the co-repressor ZMYND11 (BS69). Furthermore, ZMYND11 expression levels in patient tumors correlated with oncogenic versus tumor suppressive roles of ETS2. Therefore, these data indicate a novel and specific mechanism allowing ETS2 to switch between oncogenic and tumor suppressive functions in a cell-type specific manner.


Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Transporte/genética , Neoplasias Pulmonares/genética , Neoplasias da Próstata/genética , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-2/genética , Células A549 , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proteínas Correpressoras , Proteínas de Ligação a DNA , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Especificidade de Órgãos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Ligação Proteica , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proteína Proto-Oncogênica c-ets-2/metabolismo , Transdução de Sinais , Análise de Sobrevida , Transcrição Gênica , Proteínas ras/genética , Proteínas ras/metabolismo
9.
Methods Mol Biol ; 1487: 277-288, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27924575

RESUMO

Identifying gene expression changes mediated by signaling pathways is necessary to determine mechanisms that cause phenotypic change. Recent advances in next-generation sequencing and informatic pipelines have streamlined the ability for laboratories to create and analyze transcriptomic data. Here, we describe the preparation of samples and transcriptomic analysis in order to determine gene expression programs regulated by RAS/ERK signaling.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Estudo de Associação Genômica Ampla , Transdução de Sinais , Proteínas ras/metabolismo , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Transcriptoma
10.
Cell Rep ; 17(5): 1289-1301, 2016 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-27783944

RESUMO

More than 50% of prostate tumors have a chromosomal rearrangement resulting in aberrant expression of an oncogenic ETS family transcription factor. However, mechanisms that differentiate the function of oncogenic ETS factors expressed in prostate tumors from non-oncogenic ETS factors expressed in normal prostate are unknown. Here, we find that four oncogenic ETS (ERG, ETV1, ETV4, and ETV5), and no other ETS, interact with the Ewing's sarcoma breakpoint protein, EWS. This EWS interaction was necessary and sufficient for oncogenic ETS functions including gene activation, cell migration, clonogenic survival, and transformation. Significantly, the EWS interacting region of ERG has no homology with that of ETV1, ETV4, and ETV5. Therefore, this finding may explain how divergent ETS factors have a common oncogenic function. Strikingly, EWS is fused to various ETS factors by the chromosome translocations that cause Ewing's sarcoma. Therefore, these findings link oncogenic ETS function in both prostate cancer and Ewing's sarcoma.


Assuntos
Rearranjo Gênico/genética , Oncogenes , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Ewing/patologia , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Nus , Fenótipo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Fatores de Transcrição/metabolismo
11.
Mol Cell Biol ; 35(1): 88-100, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25332240

RESUMO

JUN transcription factors bind DNA as part of the AP-1 complex, regulate many cellular processes, and play a key role in oncogenesis. The three JUN proteins (c-JUN, JUNB, and JUND) can have both redundant and unique functions depending on the biological phenotype and cell type assayed. Mechanisms that allow this dynamic switching between overlapping and distinct functions are unclear. Here we demonstrate that JUND has a role in prostate cell migration that is the opposite of c-JUN's and JUNB's. RNA sequencing reveals that opposing regulation by c-JUN and JUND defines a subset of AP-1 target genes with cell migration roles. cis-regulatory elements for only this subset of targets were enriched for ETS factor binding, indicating a specificity mechanism. Interestingly, the function of c-JUN and JUND in prostate cell migration switched when we compared cells with an inactive versus an active RAS/extracellular signal-regulated kinase (ERK) signaling pathway. We show that this switch is due to phosphorylation and activation of JUND by ERK. Thus, the ETS/AP-1 sequence defines a unique gene expression program regulated by the relative levels of JUN proteins and RAS/ERK signaling. This work provides a rationale for how transcription factors can have distinct roles depending on the signaling status and the biological function in question.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Células HEK293 , Humanos , Células K562 , Masculino , Fosforilação , Neoplasias da Próstata/metabolismo , Ligação Proteica , Análise de Sequência de RNA , Fatores de Transcrição/metabolismo , Proteínas ras/metabolismo
12.
Nucleic Acids Res ; 42(19): 11928-40, 2014 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-25294825

RESUMO

The RAS/ERK pathway is commonly activated in carcinomas and promotes oncogenesis by altering transcriptional programs. However, the array of cis-regulatory elements and trans-acting factors that mediate these transcriptional changes is still unclear. Our genome-wide analysis determined that a sequence consisting of neighboring ETS and AP-1 transcription factor binding sites is enriched near cell migration genes activated by RAS/ERK signaling in epithelial cells. In vivo screening of candidate ETS proteins revealed that ETS1 is specifically required for migration of RAS/ERK activated cells. Furthermore, both migration and transcriptional activation through ETS/AP-1 required ERK phosphorylation of ETS1. Genome-wide mapping of multiple ETS proteins demonstrated that ETS1 binds specifically to enhancer ETS/AP-1 sequences. ETS1 occupancy, and its role in cell migration, was conserved in epithelial cells derived from multiple tissues, consistent with a chromatin organization common to epithelial cell lines. Genome-wide expression analysis showed that ETS1 was required for activation of RAS-regulated cell migration genes, but also identified a surprising role for ETS1 in the repression of genes such as DUSP4, DUSP6 and SPRY4 that provide negative feedback to the RAS/ERK pathway. Consistently, ETS1 was required for robust RAS/ERK pathway activation. Therefore, ETS1 has dual roles in mediating epithelial-specific RAS/ERK transcriptional functions.


Assuntos
Movimento Celular/genética , Células Epiteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Elementos Reguladores de Transcrição , Sítios de Ligação , Células CACO-2 , Carcinoma/genética , Linhagem Celular Tumoral , Células Cultivadas , Células Epiteliais/enzimologia , Células Epiteliais/fisiologia , Genoma Humano , Humanos , Proteína Proto-Oncogênica c-ets-1/fisiologia , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Proto-Oncogênicas c-ets/fisiologia , Fator de Transcrição AP-1/metabolismo , Ativação Transcricional
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