RESUMO
Resistance to neoadjuvant chemotherapy leads to poor prognosis of locally advanced rectal cancer (LARC), representing an unmet clinical need that demands further exploration of therapeutic strategies to improve clinical outcomes. Here, we identified a noncanonical role of RB1 for modulating chromatin activity that contributes to oxaliplatin resistance in colorectal cancer (CRC). We demonstrate that oxaliplatin induces RB1 phosphorylation, which is associated with the resistance to neoadjuvant oxaliplatin-based chemotherapy in LARC. Inhibition of RB1 phosphorylation by CDK4/6 inhibitor results in vulnerability to oxaliplatin in both intrinsic and acquired chemoresistant CRC. Mechanistically, we show that RB1 modulates chromatin activity through the TEAD4/HDAC1 complex to epigenetically suppress the expression of DNA repair genes. Antagonizing RB1 phosphorylation through CDK4/6 inhibition enforces RB1/TEAD4/HDAC1 repressor activity, leading to DNA repair defects, thus sensitizing oxaliplatin treatment in LARC. Our study identifies a RB1 function in regulating chromatin activity through TEAD4/HDAC1. It also provides the combination of CDK4/6 inhibitor with oxaliplatin as a potential synthetic lethality strategy to mitigate oxaliplatin resistance in LARC, whereby phosphorylated RB1/TEAD4 can serve as potential biomarkers to guide the patient stratification.
Assuntos
Terapia Neoadjuvante , Neoplasias Retais , Humanos , Oxaliplatina/farmacologia , Terapia Neoadjuvante/métodos , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/genética , Quimiorradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cromatina , Resultado do Tratamento , Fatores de Transcrição de Domínio TEA , Ubiquitina-Proteína Ligases , Proteínas de Ligação a RetinoblastomaRESUMO
BACKGROUND: Enhancer of zeste homolog 2 (EZH2), the key catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed and plays an oncogenic role in various cancers through catalysis-dependent or catalysis-independent pathways. However, the related mechanisms contributing to ovarian cancer (OC) are not well understood. METHODS: The levels of EZH2 and H3K27me3 were evaluated in 105 OC patients by immunohistochemistry (IHC) staining, and these patients were stratified based on these levels. Canonical and noncanonical binding sites of EZH2 were defined by chromatin immunoprecipitation sequencing (ChIP-Seq). The EZH2 solo targets were obtained by integrative analysis of ChIP-Seq and RNA sequencing data. In vitro and in vivo experiments were performed to determine the role of EZH2 in OC growth. RESULTS: We showed that a subgroup of OC patients with high EZH2 expression but low H3K27me3 exhibited the worst prognosis, with limited therapeutic options. We demonstrated that induction of EZH2 degradation but not catalytic inhibition profoundly blocked OC cell proliferation and tumorigenicity in vitro and in vivo. Integrative analysis of genome-wide chromatin and transcriptome profiles revealed extensive EZH2 occupancy not only at genomic loci marked by H3K27me3 but also at promoters independent of PRC2, indicating a noncanonical role of EZH2 in OC. Mechanistically, EZH2 transcriptionally upregulated IDH2 to potentiate metabolic rewiring by enhancing tricarboxylic acid cycle (TCA cycle) activity, which contributed to the growth of OC. CONCLUSIONS: These data reveal a novel oncogenic role of EZH2 in OC and identify potential therapeutic strategies for OC by targeting the noncatalytic activity of EZH2.
Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste , Neoplasias Ovarianas , Humanos , Feminino , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Histonas/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Neoplasias Ovarianas/patologia , Metilação , Linhagem Celular TumoralRESUMO
Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.
Assuntos
Aurora Quinase A , Proteína de Ligação a CREB , Proteínas Proto-Oncogênicas c-myc , Mutações Sintéticas Letais , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Aurora Quinase A/antagonistas & inibidores , Humanos , Animais , Camundongos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Apoptose/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Loss of ferroptosis contributes to the development of human cancer, and restoration of ferroptosis has been demonstrated as a potential therapeutic strategy in cancer treatment. However, the mechanisms of how ferroptosis escape contributes to ovarian cancer (OV) development are not well elucidated. Here, we show that ferroptosis negative regulation signatures correlated with the tumorigenesis of OV and were associated with poor prognosis, suggesting that restoration of ferroptosis represents a potential therapeutic strategy in OV. High-throughput drug screening with a kinase inhibitor library identified MEK inhibitors as ferroptosis inducers in OV cells. We further demonstrated that MEK inhibitor-resistant OV cells were less vulnerable to trametinib-induced ferroptosis. Mechanistically, mTOR/eIF4E binding protein 1 (4EBP1) signaling promoted solute carrier family 7 member 11 (SLC7A11) protein synthesis, leading to ferroptosis inhibition in MEK inhibitor-resistant cells. Dual inhibition of MEK and mTOR/4EBP1 signaling restrained the protein synthesis of SLC7A11 via suppression of the mTOR/4EBP1 axis to reactivate ferroptosis in resistant cells. Together, these findings provide a promising therapeutic option for OV treatment through ferroptosis restoration by the combined inhibition of MEK and mTOR/4EBP1 pathways.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Sistema y+ de Transporte de Aminoácidos , Ferroptose , Neoplasias Ovarianas , Inibidores de Proteínas Quinases , Serina-Treonina Quinases TOR , Ferroptose/efeitos dos fármacos , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Linhagem Celular Tumoral , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Animais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Transdução de Sinais/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêuticoRESUMO
BACKGROUND: Natural killer/T-cell lymphoma (NKTL) is a rare type of aggressive and heterogeneous non-Hodgkin's lymphoma (NHL) with a poor prognosis and limited therapeutic options. Therefore, there is an urgent need to exploit potential novel therapeutic targets for the treatment of NKTL. Histone deacetylase (HDAC) inhibitor chidamide was recently approved for treating relapsed/refractory peripheral T-cell lymphoma (PTCL) patients. However, its therapeutic efficacy in NKTL remains unclear. METHODS: We performed a phase II clinical trial to evaluate the efficacy of chidamide in 28 relapsed/refractory NKTL patients. Integrative transcriptomic, chromatin profiling analysis and functional studies were performed to identify potential predictive biomarkers and unravel the mechanisms of resistance to chidamide. Immunohistochemistry (IHC) was used to validate the predictive biomarkers in tumors from the clinical trial. RESULTS: We demonstrated that chidamide is effective in treating relapsed/refractory NKTL patients, achieving an overall response and complete response rate of 39 and 18%, respectively. In vitro studies showed that hyperactivity of JAK-STAT signaling in NKTL cell lines was associated with the resistance to chidamide. Mechanistically, our results revealed that aberrant JAK-STAT signaling remodels the chromatin and confers resistance to chidamide. Subsequently, inhibition of JAK-STAT activity could overcome resistance to chidamide by reprogramming the chromatin from a resistant to sensitive state, leading to synergistic anti-tumor effect in vitro and in vivo. More importantly, our clinical data demonstrated that combinatorial therapy with chidamide and JAK inhibitor ruxolitinib is effective against chidamide-resistant NKTL. In addition, we identified TNFRSF8 (CD30), a downstream target of the JAK-STAT pathway, as a potential biomarker that could predict NKTL sensitivity to chidamide. CONCLUSIONS: Our study suggests that chidamide, in combination with JAK-STAT inhibitors, can be a novel targeted therapy in the standard of care for NKTL. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02878278. Registered 25 August 2016, https://clinicaltrials.gov/ct2/show/NCT02878278.
Assuntos
Linfoma de Células T Periférico , Neoplasias , Humanos , Biomarcadores , Linhagem Celular Tumoral , Cromatina , Montagem e Desmontagem da Cromatina , Metilação de DNA , Janus Quinases/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/genética , Transdução de Sinais , Fatores de Transcrição STAT/uso terapêuticoRESUMO
Prevalent copy number alteration is the most prominent genetic characteristic associated with ovarian cancer (OV) development, but its role in immune evasion has not been fully elucidated. In this study, we identified RAD21, a key component of the cohesin complex, as a frequently amplified oncogene that could modulate immune response in OV. Through interrogating the RAD21-regulated transcriptional program, we found that RAD21 directly interacts with YAP/TEAD4 transcriptional corepressors and recruits the NuRD complex to suppress interferon (IFN) signaling. In multiple clinical cohorts, RAD21 overexpression is inversely correlated with IFN signature gene expression in OV. We further demonstrated in murine syngeneic tumor models that RAD21 ablation potentiated anti-PD-1 efficacy with increased intratumoral CD8+ T cell effector activity. Our study identifies a RAD21-YAP/TEAD4-NuRD corepressor complex in immune modulation, and thus provides a potential target and biomarker for precision immunotherapy in OV.
Assuntos
Proteínas de Ciclo Celular , Neoplasias Ovarianas , Camundongos , Animais , Feminino , Humanos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a DNA/genética , Evasão da Resposta Imune , Fatores de Transcrição/genética , Neoplasias Ovarianas/genética , Interferons/genética , Proteínas MuscularesRESUMO
Dysregulation of the cell cycle machinery leads to genomic instability and is a hallmark of cancer associated with chemoresistance and poor prognosis in colorectal cancer (CRC). Identifying and targeting aberrant cell cycle machinery is expected to improve current therapies for CRC patients. Here,upregulated polo-like kinase 1 (PLK1) signaling, accompanied by deregulation of cell cycle-related pathways in CRC is identified. It is shown that aberrant PLK1 signaling correlates with recurrence and poor prognosis in CRC patients. Genetic and pharmacological blockade of PLK1 significantly increases the sensitivity to oxaliplatin in vitro and in vivo. Mechanistically, transcriptomic profiling analysis reveals that cell cycle-related pathways are activated by oxaliplatin treatment but suppressed by a PLK1 inhibitor. Cell division cycle 7 (CDC7) is further identified as a critical downstream effector of PLK1 signaling, which is transactivated via the PLK1-MYC axis. Increased CDC7 expression is also found to be positively correlated with aberrant PLK1 signaling in CRC and is associated with poor prognosis. Moreover, a CDC7 inhibitor synergistically enhances the anti-tumor effect of oxaliplatin in CRC models, demonstrating the potential utility of targeting the PLK1-MYC-CDC7 axis in the treatment of oxaliplatin-based chemotherapy.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Oxaliplatina/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Quinase 1 Polo-LikeRESUMO
Ovarian cancer is characterized by aberrant activation of the mitogen-activated protein kinase (MAPK), highlighting the importance of targeting the MAPK pathway as an attractive therapeutic strategy. However, the clinical efficacy of MEK inhibitors is limited by intrinsic or acquired drug resistance. Here, we established patient-derived ovarian cancer models resistant to MEK inhibitors and demonstrated that resistance to the clinically approved MEK inhibitor trametinib was associated with enhancer reprogramming. We also showed that enhancer decommissioning induced the downregulation of negative regulators of the MAPK pathway, leading to constitutive ERK activation and acquired resistance to trametinib. Epigenetic compound screening uncovered that HDAC inhibitors could alter the enhancer reprogramming and upregulate the expression of MAPK negative regulators, resulting in sustained MAPK inhibition and reversal of trametinib resistance. Consequently, a combination of HDAC inhibitor and trametinib demonstrated a synergistic antitumor effect in vitro and in vivo, including patient-derived xenograft mouse models. These findings demonstrated that enhancer reprogramming of the MAPK regulatory pathway might serve as a potential mechanism underlying MAPK inhibitor resistance and concurrent targeting of epigenetic pathways and MAPK signaling might provide an effective treatment strategy for advanced ovarian cancer.
Assuntos
Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Elementos Facilitadores Genéticos , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Piridonas/farmacologia , Pirimidinonas/farmacologiaRESUMO
Diffuse large B-cell lymphoma (DLBCL) exhibits frequent inactivating mutations of the histone acetyltransferase CREBBP, highlighting the attractiveness of targeting CREBBP deficiency as a therapeutic strategy. In this study, we demonstrate that chidamide, a novel histone deacetylase (HDAC) inhibitor, is effective in treating a subgroup of relapsed/refractory DLBCL patients, achieving an overall response rate (ORR) of 25.0% and a complete response (CR) rate of 15.0%. However, the clinical response to chidamide remains poor, as most patients exhibit resistance, hampering the clinical utility of the drug. Functional in vitro and in vivo studies have shown that CREBBP loss of function is correlated with chidamide sensitivity, which is associated with modulation of the cell cycle machinery. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators identified AURKA inhibitors, which inhibit the G2/M transition during the cell cycle, as top candidates that synergistically enhanced the antitumor effects of chidamide in CREBBP-proficient DLBCL cells. Our study demonstrates that CREBBP inactivation can serve as a potential biomarker to predict chidamide sensitivity, while combination of an AURKA inhibitor and chidamide is a novel therapeutic strategy for the treatment of relapsed/refractory DLBCL.