Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Cell ; 184(15): 4032-4047.e31, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34171309

RESUMO

Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.


Assuntos
Neoplasias/genética , Neoplasias/imunologia , Splicing de RNA/genética , Animais , Apresentação de Antígeno/efeitos dos fármacos , Apresentação de Antígeno/imunologia , Antígenos de Neoplasias/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Epitopos/imunologia , Etilenodiaminas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia , Inflamação/patologia , Camundongos Endogâmicos C57BL , Peptídeos/metabolismo , Isoformas de Proteínas/metabolismo , Pirróis/farmacologia , Splicing de RNA/efeitos dos fármacos , Sulfonamidas/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
2.
Nat Cancer ; 3(7): 837-851, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35668193

RESUMO

Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment. We discover that selinexor activates PI3Kγ-dependent AKT signaling in AML by upregulating the purinergic receptor P2RY2. Inhibiting this axis potentiates the anti-leukemic effects of selinexor in AML cell lines, patient-derived primary cultures and multiple mouse models of AML. In a syngeneic, MLL-AF9-driven mouse model of AML, treatment with selinexor and ipatasertib outperforms both standard-of-care chemotherapy and chemotherapy with selinexor. Together, these findings establish drug-induced P2RY2-AKT signaling as an actionable consequence of XPO1 inhibition in AML.


Assuntos
Leucemia Mieloide Aguda , Proteínas Proto-Oncogênicas c-akt , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Carioferinas/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Estados Unidos , Proteína Exportina 1
3.
Nat Genet ; 52(4): 408-417, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203462

RESUMO

Local adaptation directs populations towards environment-specific fitness maxima through acquisition of positively selected traits. However, rapid environmental changes can identify hidden fitness trade-offs that turn adaptation into maladaptation, resulting in evolutionary traps. Cancer, a disease that is prone to drug resistance, is in principle susceptible to such traps. We therefore performed pooled CRISPR-Cas9 knockout screens in acute myeloid leukemia (AML) cells treated with various chemotherapies to map the drug-dependent genetic basis of fitness trade-offs, a concept known as antagonistic pleiotropy (AP). We identified a PRC2-NSD2/3-mediated MYC regulatory axis as a drug-induced AP pathway whose ability to confer resistance to bromodomain inhibition and sensitivity to BCL-2 inhibition templates an evolutionary trap. Across diverse AML cell-line and patient-derived xenograft models, we find that acquisition of resistance to bromodomain inhibition through this pathway exposes coincident hypersensitivity to BCL-2 inhibition. Thus, drug-induced AP can be leveraged to design evolutionary traps that selectively target drug resistance in cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Pleiotropia Genética/genética , Neoplasias/genética , Adaptação Fisiológica/genética , Animais , Evolução Biológica , Sistemas CRISPR-Cas/genética , Linhagem Celular , Linhagem Celular Tumoral , Meio Ambiente , Aptidão Genética/genética , Células HEK293 , Células HL-60 , Humanos , Camundongos , Proteínas Nucleares/genética , Fenótipo , Locos de Características Quantitativas/genética , Fatores de Transcrição/genética
4.
Cell Metab ; 29(5): 1217-1231.e7, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30773463

RESUMO

Crosstalk between metabolic and survival pathways is critical for cellular homeostasis, but the connectivity between these processes remains poorly defined. We used loss-of-function CRISPR/Cas9 knockout screening to identify metabolic genes capable of influencing cellular commitment to apoptosis, using sensitization to the BCL-2 inhibitor ABT-199 in BCL-2-dependent acute myeloid leukemia (AML) cell lines as a proxy for apoptotic disposition. This analysis revealed metabolic pathways that specifically cooperate with BCL-2 to sustain survival. In particular, our analysis singled out heme biosynthesis as an unappreciated apoptosis-modifying pathway. Although heme is broadly incorporated into the proteome, reduction of heme biosynthesis potentiates apoptosis through the loss of ETC activity, resulting in baseline depolarization of the mitochondrial membrane and an increased propensity to undergo apoptosis. Collectively, our findings chart the first apoptotic map of metabolism, motivating the design of metabolically engaged combination chemotherapies and nominating heme biosynthesis as an apoptotic modulator in AML.


Assuntos
Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Heme/biossíntese , Leucemia Mieloide Aguda/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Antineoplásicos/farmacologia , Apoptose/genética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Transporte de Elétrons , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Leucemia Mieloide Aguda/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Células THP-1 , Transdução Genética
5.
Sci Rep ; 6: 27696, 2016 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-27283158

RESUMO

ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-XL as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-XL. By targeting MCL-1 and BCL-XL, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-XL alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-XL and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.


Assuntos
Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Sulfonamidas/farmacologia , Proteína bcl-X/genética , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteína bcl-X/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA