Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cancer Lett ; 472: 119-131, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31866466

RESUMO

Although trastuzumab has greatly improved the outcome of HER2-positive breast cancer, the emergence of resistance hampers its clinical benefits. Trastuzumab resistance is a multi-factorial consequence predominantly due to presence of cancer stem-like cells (CSCs). AZD1775, a potent anti-cancer agent targeting WEE1 kinase to drive tumor cells with DNA damage to premature mitosis, has previously shown high efficacies when targeting different cancers with a well-tolerated cytotoxic profile, but has not been evaluated in trastuzumab-resistant (TrR) breast cancer. We sought to investigate the effect of AZD1775 on cancer stem-like cell (CSC) properties, apoptosis, cell cycle regulation in TrR breast cancer. Our study for the first time demonstrated that AZD1775 induces apoptosis and arrests TrR cells at G2/M phase. More importantly, AZD1775 effectively targeted CSC properties by suppressing MUC1 expression levels. AZD1775 administration also induced apoptosis in our in-house patient-derived tumor cell line at passage 0, implying its significant clinical relevance. These findings highlight the potential clinical application of AZD1775 in overcoming trastuzumab resistance in breast cancer.

3.
BMC Cancer ; 19(1): 1061, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31703584

RESUMO

BACKGROUND: To reveal roles of reactive oxygen species (ROS) status in chemotherapy resistance and to develop a ROS scoring system for prognosis prediction in ovarian cancer. METHODS: We tested the sensitizing effects of ROS elevating drugs to cisplatin (cDDP) in ovarian cancer both in vitro and in vivo. A ROS scoring system was developed using The Cancer Genome Atlas (TCGA) database of ovarian cancer. The associations between ROS scores and overall survival (OS) were analyzed in TCGA, Tothill dataset, and our in-house dataset (TJ dataset). RESULTS: ROS-inducing drugs increased cisplatin-induced ovarian cancer cell injury in vitro and in vivo. ROS scoring system was established using 25 ROS-related genes. Patients were divided into low (scores 0-12) and high (scores 13-25) score groups. Improved patient survival was associated with higher scores (TCGA dataset hazard ratio (HR) = 0.43, P < 0.001; Tothill dataset HR = 0.65, P = 0.022; TJ dataset HR = 0.40, P = 0.003). The score was also significantly associated with OS in multiple datasets (TCGA dataset r2 = 0.574, P = 0.032; Thothill dataset r2 = 0.266, P = 0.049; TJ dataset r2 = 0.632, P = 0.001) and with cisplatin sensitivity in ovarian cancer cell lines (r2 = 0.799, P = 0.016) when used as a continuous variable. The scoring system showed better prognostic performance than other clinical factors by receiver operating characteristic (ROC) curves (TCGA dataset area under the curve (AUC) = 0.71 v.s. 0.65, Tothill dataset AUC = 0.73 v.s. 0.67, TJ dataset AUC = 0.74 v.s. 0.66). CONCLUSIONS: ROS status is associated with chemotherapy resistance. ROS score system might be a prognostic biomarker in predicting the survival benefit from ovarian cancer patients.

4.
J Ovarian Res ; 12(1): 107, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31703731

RESUMO

BACKGROUND: Cisplatin-based chemotherapy is the first-line treatment for ovarian cancer. However, acquired resistance to cisplatin treatment often occurs in epithelial ovarian cancer, and effective and practical methods for overcoming this obstacle are urgently needed. The study aimed to demonstrate the synergistic effect of clarithromycin (CAM) with cisplatin to inhibit ovarian carcinoma cells growth in vitro and in vivo. RESULTS: We performed CCK-8 assay to detect apoptosis rates in response to CAM alone or in combination with cisplatin, which were further confirmed by Annexin V and PI staining methods and western blotting. Mechanistically, CAM could reduce endogenous antioxidant enzyme expression and increase the levels of reactive oxygen species (ROS) to augment the cytotoxic effect of cisplatin. Meanwhile, a tumor xenograft model in athymic BALB/c-nude mice demonstrated that CAM combined with cisplatin resulted in reduced tumor growth and weight compared with cisplatin alone. CONCLUSION: Collectively, our results indicate that CAM works synergistically with cisplatin to inhibit ovarian cancer cell growth, which may be manipulated by a ROS-mediated mechanism that enhances cisplatin therapy, and offers a novel strategy for overcoming cisplatin therapy resistance.

5.
Oncogene ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31705064

RESUMO

Ovarian cancer selective metastasizes to the omentum contributing to the poor prognosis associated with ovarian cancer. However, the mechanism underlining this propensity and therapeutic approaches to counter this process has not been fully elucidated. Here, we show that MCP-1 produced by omental adipocytes binding to its cognate receptor CCR-2 on ovarian cancer cells facilitates migration and omental metastasis by activating the PI3K/AKT/mTOR pathway and its downstream effectors HIF-1α and VEGF-A in cell lines, xenografts, and transgenic murine models. MCP-1 antibody significantly decreased tumor burden and increased survival of mice in vivo. Interestingly, metformin decreased omental metastasis at least partially by inhibiting MCP-1 secretion from adipocytes independent of direct effects on cancer cells. Together this suggests a novel target of MCP-1/CCR-2 axis that could benefit ovarian cancer patients.

6.
Oncol Rep ; 42(6): 2768-2776, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638241

RESUMO

Ovarian cancer (OC) is highly metastatic due to frequent peritoneal dissemination, and its treatment poses a major challenge in clinical practice. Yes­associated protein (YAP) is known to be associated with the development of multiple tumors. However, whether targeting YAP can restrain OC progression and the underlying mechanisms have yet to be fully elucidated. In the present study, YAP was found to be highly expressed in OC, and its expression was correlated with the prognosis of OC patients. Moreover, silencing of YAP markedly inhibited the malignant behavior of OC cells, possibly through regulation of the PI3K/Akt/mTOR pathway. Notably, peptide 17, a YAP inhibitor, exerted a significant attenuating effect on OC progression by diminishing the activation of the PI3K/Akt/mTOR pathway in vitro as well as in vivo. Taken together, these findings demonstrated that targeting YAP attenuated OC progression and suggested the potential application of peptide 17 in OC therapy, thus providing new insights into improving the treatment of OC.

8.
Clin Cancer Res ; 25(22): 6827-6838, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31383732

RESUMO

PURPOSE: Despite the FDA approval of mTOR inhibitors (mTORi) for the treatment of renal cell carcinoma (RCC), the benefits are relatively modest and the few responders usually develop resistance. We investigated whether the resistance to mTORi is due to upregulation of PD-L1 and the underlying molecular mechanism. EXPERIMENTAL DESIGN: The effects of transcription factor EB (TFEB) on RCC proliferation, apoptosis, and migration were evaluated. Correlation of TFEB with PD-L1 expression, as well as effects of mTOR inhibition on TFEB and PD-L1 expression, was assessed in human primary clear cell RCCs. The regulation of TFEB on PD-L1 was assessed by chromatin immunoprecipitation and luciferase reporter assay. The therapeutic efficacies of mTORi plus PD-L1 blockade were evaluated in a mouse model. The function of tumor-infiltrating CD8+ T cells was analyzed by flow cytometry. RESULTS: TFEB did not affect tumor cell proliferation, apoptosis, and migration. We found a positive correlation between TFEB and PD-L1 expression in RCC tumor tissues, primary tumor cells, and RCC cells. TFEB bound to PD-L1 promoter in RCCs and inhibition of mTOR led to enhanced TFEB nuclear translocation and PD-L1 expression. Simultaneous inhibition of mTOR and blockade of PD-L1 enhanced CD8+ cytolytic function and tumor suppression in a xenografted mouse model of RCC. CONCLUSIONS: These data revealed that TFEB mediates resistance to mTOR inhibition via induction of PD-L1 in human primary RCC tumors, RCC cells, and murine xenograft model. Our data provide a strong rationale to target mTOR and PD-L1 jointly as a novel immunotherapeutic approach for RCC treatment.

10.
Cancer Cell ; 35(6): 851-867.e7, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185210

RESUMO

We demonstrate that concurrent administration of poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors is effective in inhibiting tumor growth but poorly tolerated. Concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage, and abrogates the G2 DNA damage checkpoint in both normal and malignant cells. Following cessation of monotherapy with PARP or WEE1 inhibitors, effects of these inhibitors persist suggesting that sequential administration of PARP and WEE1 inhibitors could maintain efficacy while ameliorating toxicity. Strikingly, while sequential administration mirrored concurrent therapy in cancer cells that have high basal replication stress, low basal replication stress in normal cells protected them from DNA damage and toxicity, thus improving tolerability while preserving efficacy in ovarian cancer xenograft and patient-derived xenograft models.

11.
Materials (Basel) ; 12(6)2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30889847

RESUMO

This research aims to correlate the macroscopic fracture phenomenon with its microscopic fracture mechanism for an advanced high-strength steel (AHSS) TRIP 780 sheet by applying a combined experimental-numerical approach. Six specimens with different shapes were tensioned to fracture and the main deformation areas of specimens were subjected to stress states ranging from lower to higher stress triaxiality. The final fracture surface feature for each specimen was obtained to characterize the macroscopic fracture modes at different stress states. The scanning electron microscope (SEM) fractographies of fracture surfaces were detected to reveal the microscopic fracture mechanisms. The stress triaxiality evolution was applied to correlate of fracture mode and fracture mechanism by comparing the macroscopic fracture features as well as micro-defect changes. An increase of stress triaxiality leads to voids extension and then results in a voids-dominant fracture. The micro-shear-slip tends to appear in the stress triaxiality level lower than that of pure shear stress state. The fracture behavior of a practice deformation process was the result of interplay between shear-slip fracture and void-dominant fracture. The unified relationship between average void sizes and stress triaxiality was obtained. The void growth was predicted by the Rice⁻Tracey model with higher precision.

12.
Sci Rep ; 9(1): 1691, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30737418

RESUMO

Ovarian carcinoma is caused by multiple factors, but its etiology associated with microbes and infection is unknown. Using 16S rRNA high-throughput sequencing methods, the diversity and composition of the microbiota from ovarian cancer tissues (25 samples) and normal distal fallopian tube tissues (25 samples) were analyzed. High-throughput sequencing showed that the diversity and richness indexes were significantly decreased in ovarian cancer tissues compared to tissues from normal distal fallopian tubes. The ratio of the two phyla for Proteobacteria/Firmicutes was notably increased in ovarian cancer, which revealed that microbial composition change might be associated with the process of ovarian cancer development. In addition, transcriptome-sequencing (RNA-seq) analyses suggested that the transcriptional profiles were statistically different between ovarian carcinoma and normal distal fallopian tubes. Moreover, a set of genes including 84 different inflammation-associated or immune-associated genes, which had been named as the human antibacterial-response genes were also modulated expression. Therefore, we hypothesize that the microbial composition change, as a novel risk factor, may be involving the initiation and progression of ovarian cancer via influencing and regulating the local immune microenvironment of fallopian tubes except for regular pathways.

13.
J Exp Med ; 216(3): 688-703, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30710055

RESUMO

High-grade serous ovarian cancer (HGSOC) is hallmarked by early onset of peritoneal dissemination, which distinguishes it from low-grade serous ovarian cancer (LGSOC). Here, we describe the aggressive nature of HGSOC ascitic tumor cells (ATCs) characterized by integrin α5high (ITGA5high) ATCs, which are prone to forming heterotypic spheroids with fibroblasts. We term these aggregates as metastatic units (MUs) in HGSOC for their advantageous metastatic capacity and active involvement in early peritoneal dissemination. Intriguingly, fibroblasts inside MUs support ATC survival and guide their peritoneal invasion before becoming essential components of the tumor stroma in newly formed metastases. Cancer-associated fibroblasts (CAFs) recruit ITGA5high ATCs to form MUs, which further sustain ATC ITGA5 expression by EGF secretion. Notably, LGSOC is largely devoid of CAFs and the resultant MUs, which might explain its metastatic delay. These findings identify a specialized MU architecture that amplifies the tumor-stroma interaction and promotes transcoelomic metastasis in HGSOC, providing the basis for stromal fibroblast-oriented interventions in hampering OC peritoneal propagation.

15.
Am J Med Sci ; 355(6): 530-536, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29891036

RESUMO

BACKGROUND: The study aimed to evaluate the prognostic value of cystatin C in ST-elevation acute myocardial infarction (STEMI) patients who underwent elective percutaneous coronary intervention (PCI). METHODS: A retrospective study was conducted on 664 STEMI patients from 7 centers who were treated with elective PCI. These patients were divided into 3 groups according their admission cystatin C levels as < 0.84, 0.84-1.03 and ≥1.04mg/L. The all-cause mortalities and the composite endpoints, including mortality, reinfarction, rehospitalization for heart failure and angina or repeat target vessel revascularization were observed for up to 5 years. RESULTS: As cystatin C levels from low to high, all-cause mortalities were progressively increased 0.9%, 3.7% and 9.5% (P < 0.001), as well as the composite endpoints, 11.1%, 21.7% and 40.7%, respectively (P < 0.001). When patients had the level of cystatin C ≥0.84mg/L, their risks of composite endpoints increased 2- to 3-fold of those with <0.84mg/L, with the adjusted hazard ratio of 2.096 (95% CI: 1.047-4.196, P = 0.037) and 3.608 (95% CI: 1.939-6.716, P < 0.001), respectively. CONCLUSIONS: Increased cystatin C levels may be associated with enhanced risks of composite endpoints in patients with STEMI undergoing elective PCI.


Assuntos
Angioplastia , Cistatina C/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Idoso , Angina Instável/terapia , Angiografia Coronária , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Insuficiência Cardíaca/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Intervenção Coronária Percutânea , Prognóstico , Estudos Retrospectivos
16.
Cancer Cell ; 33(3): 401-416.e8, 2018 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-29533782

RESUMO

Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1, BRCA2, and other pathway members. We sought small molecules that induce HRD in HR-competent cells to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrated that inhibition of bromodomain containing 4 (BRD4) induced HRD and sensitized cells across multiple tumor lineages to PARPi regardless of BRCA1/2, TP53, RAS, or BRAF mutation status through depletion of the DNA double-stand break resection protein CtIP (C-terminal binding protein interacting protein). Importantly, BRD4 inhibitor (BRD4i) treatment reversed multiple mechanisms of resistance to PARPi. Furthermore, PARPi and BRD4i are synergistic in multiple in vivo models.


Assuntos
Recombinação Homóloga/genética , Proteínas Nucleares/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Feminino , Recombinação Homóloga/efeitos dos fármacos , Humanos , Camundongos Transgênicos , Mutação/efeitos dos fármacos , Mutação/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/genética , Fatores de Transcrição/genética
17.
Mol Cancer Ther ; 17(6): 1291-1302, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29545331

RESUMO

Ovarian cancer is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in ovarian cancer. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the ovarian cancer tumor cells. First, we found a significant stromal overexpression of IL6 in patient samples that received cisplatin-based treatment, which was further validated in purified fibroblasts challenged with cisplatin. Stromal fibroblast-derived IL6 was proven to mediate ovarian cancer tumor cell chemoresistance. For the first time, we found that the tumor stroma of patients with routine metformin administration exhibited lower IL6 expression. Thus, we presumed that metformin was a potent alleviator of stromal inflammation in ovarian cancer. We found that metformin partly reversed cisplatin-stimulated IL6 secretion in the stromal fibroblasts and attenuated fibroblast-facilitated tumor growth in 3D organotypic cocultures and murine xenograft models. Mechanistically, we found that metformin inhibited IL6 secretion via suppressing NFκB signaling, an upstream controller of stromal inflammation. Collectively, our findings introduced a novel mechanism of metformin in suppressing ovarian cancer progression through diminishing chemotherapy-induced stromal activation. Therefore, we provide an alternative therapeutic option in targeting stromal inflammation and a potential scheme of combination therapy to improve the chemosensitivity in ovarian cancer. Mol Cancer Ther; 17(6); 1291-302. ©2018 AACR.


Assuntos
Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Metformina/farmacologia , Neoplasias Ovarianas/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Animais , Antineoplásicos/farmacologia , Biomarcadores , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Interleucina-6/metabolismo , Camundongos , Modelos Biológicos , NF-kappa B/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
18.
Cancer Lett ; 415: 20-29, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29199004

RESUMO

Inflammation and host stromal activation contribute significantly to ovarian cancer (OC) initiation and malignant progression. However, the complex reciprocal interactions between them are largely unknown. Here, we discovered that the tumor suppressor gene Dicer was paradoxically overexpressed in ovarian tumor stroma, and induced fibroblast activation and stromal inflammation. Dicer transformed normal fibroblasts to a carcinoma-associated fibroblast (CAF)-like state, which was morphologically spread out and functionally activated to fuel tumor invasion and metastasis. Attenuation of Dicer hampered CAF characteristics, diminished stromal inflammation and the role of fibroblasts in supporting tumor growth. Moreover, Dicer drove the expression of an "inflammatory signature" in fibroblasts that could be used to discriminate normal and cancerous stroma and predict the survival of patients with OC. Finally, the nuclear factor κ B (NFκB) signaling was demonstrated to be responsible for Dicer effect on fibroblast activation and stromal inflammation, through microRNA (miR)-6780b. Our study represents the first report that characterizes Dicer expression and function in the tumor stroma, and highlights its pro-metastatic role in this context. Additionally, we suggest that the Dicer-miR6780b-NFκB cascade is an attractive target of choice in stroma-oriented OC therapy.


Assuntos
Transformação Celular Neoplásica/genética , RNA Helicases DEAD-box/genética , Fibroblastos/metabolismo , Neoplasias Ovarianas/genética , Ribonuclease III/genética , Células Estromais/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Técnicas de Cocultura , RNA Helicases DEAD-box/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Knockout , MicroRNAs/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fenótipo , Ribonuclease III/metabolismo , Transdução de Sinais/genética , Células THP-1 , Transplante Heterólogo
19.
Mol Cancer ; 16(1): 163, 2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29041931

RESUMO

BACKGROUND: Molecular profiling in ovarian cancer (OC) revealed that the desmoplasia subtype presented the poorest prognosis, highlighting the contribution of stromal fibroblasts in tumor progression. This study aimed to investigate the molecular characteristics of SNAI2 driving the transcriptional reprogramming of fibroblasts within tumors. METHODS: SNAI2 expression was evaluated in microdissected profiles of various cancers and in various molecular subtypes of OC. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were performed to explore the correlation between SNAI2 and stromal fibroblast activation. The SNAI2 defined signature in the mesenchymal OC subtype was identified through an integrative analysis of the TCGA and the Tothill datasets. The predictive value of this signature was validated in independent datasets. SNAI2 expression alteration influence of tumor growth in primary CAFs was evaluated in 3D organotypic and murine xenograft models. RESULTS: We demonstrated that SNAI2 was frequently activated in the tumor stroma, correlated with fibroblast activation and worse patient outcome in OC. SNAI2 transformed normal fibroblasts to a CAF-like state and boosted their tumor-supporting role in 3D organotypic culture and in OC xenograft model. SNAI2 drove a transcriptional signature in the mesenchymal subtype of OC that contributed to tumor desmoplasia, which fed back to increase SNAI2 expression and sustain fibroblast activation. CONCLUSIONS: Our results address the role of SNAI2 in reprogramming stromal fibroblasts. The identified SNAI2 mesenchymal signature has both a predictive value and biological relevance and might be a therapeutic target for stroma-oriented therapy against the desmoplasia OC subtype.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fatores de Transcrição da Família Snail/metabolismo , Células Estromais/metabolismo , Animais , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Imuno-Histoquímica , Neoplasias Ovarianas/genética , Fatores de Transcrição da Família Snail/genética
20.
Sci Transl Med ; 9(392)2017 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-28566428

RESUMO

Mutant RAS has remained recalcitrant to targeted therapy efforts. We demonstrate that combined treatment with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple RAS mutant tumor models across tumor lineages where RAS mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of BRCA1/2 and p53 mutation status, suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in RAS mutant tumors is associated with (i) induction of BIM-mediated apoptosis, (ii) decrease in expression of components of the homologous recombination DNA repair pathway, (iii) decrease in homologous recombination DNA damage repair capacity, (iv) decrease in DNA damage checkpoint activity, (v) increase in PARP inhibitor-induced DNA damage, (vi) decrease in vascularity that could increase PARP inhibitor efficacy by inducing hypoxia, and (vii) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus, the ability of mutant RAS to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in RAS mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with RAS mutant tumors where there are few effective therapeutic options.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Genes ras , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Proteína Forkhead Box O3/metabolismo , Recombinação Homóloga/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA