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1.
Cancer Res ; 81(20): 5325-5335, 2021 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-34548333

RESUMEN

The SWI/SNF chromatin-remodeling complex is frequently altered in human cancers. For example, the SWI/SNF component ARID1A is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), for which effective treatments are lacking. Here, we report that ARID1A transcriptionally represses the IRE1α-XBP1 axis of the endoplasmic reticulum (ER) stress response, which confers sensitivity to inhibition of the IRE1α-XBP1 pathway in ARID1A-mutant OCCC. ARID1A mutational status correlated with response to inhibition of the IRE1α-XBP1 pathway. In a conditional Arid1aflox/flox/Pik3caH1047R genetic mouse model, Xbp1 knockout significantly improved survival of mice bearing OCCCs. Furthermore, the IRE1α inhibitor B-I09 suppressed the growth of ARID1A-inactivated OCCCs in vivo in orthotopic xenograft, patient-derived xenograft, and the genetic mouse models. Finally, B-I09 synergized with inhibition of HDAC6, a known regulator of the ER stress response, in suppressing the growth of ARID1A-inactivated OCCCs. These studies define the IRE1α-XBP1 axis of the ER stress response as a targetable vulnerability for ARID1A-mutant OCCCs, revealing a promising therapeutic approach for treating ARID1A-mutant ovarian cancers. SIGNIFICANCE: These findings indicate that pharmacological inhibition of the IRE1α-XBP1 pathway alone or in combination with HDAC6 inhibition represents an urgently needed therapeutic strategy for ARID1A-mutant ovarian cancers.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteínas de Unión al ADN/genética , Estrés del Retículo Endoplásmico , Endorribonucleasas/antagonistas & inhibidores , Mutación , Neoplasias Ováricas/patología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Factores de Transcripción/genética , Proteína 1 de Unión a la X-Box/antagonistas & inhibidores , Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patología , Animales , Apoptosis , Proliferación Celular , Proteínas de Unión al ADN/fisiología , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Endorribonucleasas/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasa 6/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ratones , Ratones Noqueados , Ratones Desnudos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Factores de Transcripción/fisiología , Células Tumorales Cultivadas , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismo , Proteína 1 de Unión a la X-Box/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Nat Cancer ; 2(2): 189-200, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-34085048

RESUMEN

Alterations in components of the SWI/SNF chromatin-remodeling complex occur in ~20% of all human cancers. For example, ARID1A is mutated in up to 62% of clear cell ovarian carcinoma (OCCC), a disease currently lacking effective therapies. Here we show that ARID1A mutation creates a dependence on glutamine metabolism. SWI/SNF represses glutaminase (GLS1) and ARID1A inactivation upregulates GLS1. ARID1A inactivation increases glutamine utilization and metabolism through the tricarboxylic acid cycle to support aspartate synthesis. Indeed, glutaminase inhibitor CB-839 suppresses the growth of ARID1A mutant, but not wildtype, OCCCs in both orthotopic and patient-derived xenografts. In addition, glutaminase inhibitor CB-839 synergizes with immune checkpoint blockade anti-PDL1 antibody in a genetic OCCC mouse model driven by conditional Arid1a inactivation. Our data indicate that pharmacological inhibition of glutaminase alone or in combination with immune checkpoint blockade represents an effective therapeutic strategy for cancers involving alterations in the SWI/SNF complex such as ARID1A mutations.


Asunto(s)
Adenocarcinoma de Células Claras , Neoplasias Ováricas , Adenocarcinoma de Células Claras/tratamiento farmacológico , Animales , Proteínas de Unión al ADN/genética , Femenino , Glutaminasa/genética , Glutamina/uso terapéutico , Humanos , Inhibidores de Puntos de Control Inmunológico , Ratones , Proteínas Nucleares/genética , Neoplasias Ováricas/tratamiento farmacológico , Factores de Transcripción/genética
3.
Cancer Res ; 80(4): 890-900, 2020 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-31857293

RESUMEN

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Platinum-based chemotherapy induces cellular senescence. Notably, therapy-induced senescence contributes to chemoresistance by inducing cancer stem-like cells (CSC). However, therapeutic approaches targeting senescence-associated CSCs remain to be explored. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT) inhibition suppresses senescence-associated CSCs induced by platinum-based chemotherapy in EOC. Clinically applicable NAMPT inhibitors suppressed the outgrowth of cisplatin-treated EOC cells both in vitro and in vivo. Moreover, a combination of the NAMPT inhibitor FK866 and cisplatin improved the survival of EOC-bearing mice. These phenotypes correlated with inhibition of the CSCs signature, which consists of elevated expression of ALDH1A1 and stem-related genes, high aldehyde dehydrogenase activity, and CD133 positivity. Mechanistically, NAMPT regulates EOC CSCs in a paracrine manner through the senescence-associated secretory phenotype. Our results suggest that targeting NAMPT using clinically applicable NAMPT inhibitors, such as FK866, in conjunction with platinum-based chemotherapy represents a promising therapeutic strategy by suppressing therapy-induced senescence-associated CSCs. SIGNIFICANCE: This study highlights the importance of NAMPT-mediated NAD+ biosynthesis in the production of cisplatin-induced senescence-associated cancer stem cells, as well as tumor relapse after cisplatin treatment.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Neoplasias Ováricas/tratamiento farmacológico , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Familia de Aldehído Deshidrogenasa 1/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Senescencia Celular/efectos de los fármacos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Citocinas/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Ratones , Células Madre Neoplásicas/patología , Nicotinamida Fosforribosiltransferasa/metabolismo , Neoplasias Ováricas/patología , Piperidinas/farmacología , Piperidinas/uso terapéutico , Retinal-Deshidrogenasa/metabolismo , Esferoides Celulares , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Cancer Res ; 79(21): 5482-5489, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31311810

RESUMEN

ARID1A, encoding a subunit of the SWI/SNF complex, is the most frequently mutated epigenetic regulator in human cancers and is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), a disease that currently has no effective therapy. Inhibition of histone deacetylase 6 (HDAC6) suppresses the growth of ARID1A-mutated tumors and modulates tumor immune microenvironment. Here, we show that inhibition of HDAC6 synergizes with anti-PD-L1 immune checkpoint blockade in ARID1A-inactivated ovarian cancer. ARID1A directly repressed transcription of CD274, the gene encoding PD-L1. Reduced tumor burden and improved survival were observed in ARID1Aflox/flox/PIK3CAH1047R OCCC mice treated with the HDAC6 inhibitor ACY1215 and anti-PD-L1 immune checkpoint blockade as a result of activation and increased presence of IFNγ-positive CD8 T cells. We confirmed that the combined treatment limited tumor progression in a cytotoxic T-cell-dependent manner, as depletion of CD8+ T cells abrogated these antitumor effects. Together, these findings indicate that combined HDAC6 inhibition and immune checkpoint blockade represents a potential treatment strategy for ARID1A-mutated cancers. SIGNIFICANCE: These findings offer a mechanistic rationale for combining epigenetic modulators and existing immunotherapeutic interventions against a disease that has been so far resistant to checkpoint blockade as a monotherapy.See related commentary by Prokunina-Olsson, p. 5476.


Asunto(s)
Adenocarcinoma de Células Claras , Neoplasias Ováricas , Animales , Antígeno B7-H1 , Linfocitos T CD8-positivos , Proteínas de Unión al ADN , Femenino , Histona Desacetilasa 6 , Humanos , Ratones , Proteínas Nucleares , Factores de Transcripción , Microambiente Tumoral
5.
Cancer Res ; 76(8): 2137-52, 2016 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-26951929

RESUMEN

Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In Eµ-TCL1 mice with chronic lymphocytic leukemia, injection of the STING agonist 3'3'-cGAMP induced apoptosis and tumor regression. Similarly efficacious effects were elicited by 3'3'-cGAMP injection in syngeneic or immunodeficient mice grafted with multiple myeloma. Thus, in addition to their established ability to boost antitumoral immune responses, STING agonists can also directly eradicate malignant B cells. Cancer Res; 76(8); 2137-52. ©2016 AACR.


Asunto(s)
Apoptosis/fisiología , Linfocitos B/metabolismo , Proteínas de la Membrana/agonistas , Animales , Linfocitos B/citología , Línea Celular , GMP Cíclico/administración & dosificación , GMP Cíclico/farmacología , Inyecciones Intraperitoneales , Proteínas de la Membrana/fisiología , Ratones
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