RESUMEN
PURPOSE: In preclinical models, glucocorticoid receptor (GR) signaling drives resistance to taxane chemotherapy in multiple solid tumors via upregulation of anti-apoptotic pathways. ORIC-101 is a potent and selective GR antagonist that was investigated in combination with taxane chemotherapy as an anticancer regimen preclinically and in a phase 1 clinical trial. PATIENTS AND METHODS: The ability of ORIC-101 to reverse taxane resistance was assessed in cell lines and xenograft models, and a phase 1 study (NCT03928314) was conducted in patients with advanced solid tumors to determine the dose, safety, and antitumor activity of ORIC-101 with nab-paclitaxel. RESULTS: ORIC-101 reversed chemoprotection induced by glucocorticoids in vitro and achieved tumor regressions when combined with paclitaxel in both taxane-naïve and -resistant xenograft models. In the phase 1 study, 21 patients were treated in dose escalation and 62 patients were treated in dose expansion. All patients in dose expansion had previously progressed on a taxane-based regimen. In dose escalation, 5 objective responses were observed. A pre-planned futility analysis in dose expansion showed a 3.2% (95% CI 0.4, 11.2) ORR with a median PFS of 2 months (95% CI 1.8, 2.8) across all 4 cohorts, leading to study termination. Pharmacodynamic analysis of tissue and plasma showed GR pathway downregulation in most patients in cycle 1. CONCLUSIONS: ORIC-101 with nab-paclitaxel showed limited clinical activity in taxane-resistant solid tumors. Despite clear inhibition of GR pathway signaling, the insufficient clinical signal underscores the challenges of targeting a single resistance pathway when multiple mechanisms of resistance may be in play.
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Molecular profiling guides precision treatment of breast cancer; however, Asian patients are underrepresented in publicly available large-scale studies. We established a comprehensive multiomics cohort of 773 Chinese patients with breast cancer and systematically analyzed their genomic, transcriptomic, proteomic, metabolomic, radiomic and digital pathology characteristics. Here we show that compared to breast cancers in white individuals, Asian individuals had more targetable AKT1 mutations. Integrated analysis revealed a higher proportion of HER2-enriched subtype and correspondingly more frequent ERBB2 amplification and higher HER2 protein abundance in the Chinese HR+HER2+ cohort, stressing anti-HER2 therapy for these individuals. Furthermore, comprehensive metabolomic and proteomic analyses revealed ferroptosis as a potential therapeutic target for basal-like tumors. The integration of clinical, transcriptomic, metabolomic, radiomic and pathological features allowed for efficient stratification of patients into groups with varying recurrence risks. Our study provides a public resource and new insights into the biology and ancestry specificity of breast cancer in the Asian population, offering potential for further precision treatment approaches.
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Pueblo Asiatico , Neoplasias de la Mama , Receptor ErbB-2 , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Femenino , Pueblo Asiatico/genética , Receptor ErbB-2/genética , Mutación , Proteómica/métodos , Perfilación de la Expresión Génica/métodos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Persona de Mediana Edad , China/epidemiología , Ferroptosis/genética , Adulto , Metabolómica/métodos , Transcriptoma , Biomarcadores de Tumor/genética , Pueblos del Este de AsiaRESUMEN
PURPOSE: Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist. PATIENTS AND METHODS: Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D). RESULTS: A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65-38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation. CONCLUSIONS: Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.
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Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores de Glucocorticoides , Feniltiohidantoína , Benzamidas/uso terapéutico , Nitrilos/uso terapéutico , Antineoplásicos Hormonales/uso terapéuticoRESUMEN
The FOXA1 pioneer factor is an essential mediator of steroid receptor function in multiple hormone-dependent cancers, including breast and prostate cancers, enabling nuclear receptors such as estrogen receptor (ER) and androgen receptor (AR) to activate lineage-specific growth programs. FOXA1 is also highly expressed in non-small cell lung cancer (NSCLC), but whether and how it regulates tumor growth in this context is not known. Analyzing data from loss-of-function screens, we identified a subset of NSCLC tumor lines where proliferation is FOXA1 dependent. Using rapid immunoprecipitation and mass spectrometry of endogenous protein, we identified chromatin-localized interactions between FOXA1 and glucocorticoid receptor (GR) in these tumor cells. Knockdown of GR inhibited proliferation of FOXA1-dependent, but not FOXA1-independent NSCLC cells. In these FOXA1-dependent models, FOXA1 and GR cooperate to regulate gene targets involved in EGF signaling and G1-S cell-cycle progression. To investigate the therapeutic potential for targeting this complex, we examined the effects of highly selective inhibitors of the GR ligand-binding pocket and found that GR antagonism with ORIC-101 suppressed FOXA1/GR target expression, activation of EGF signaling, entry into the S-phase, and attendant proliferation in vitro and in vivo. Taken together, our findings point to a subset of NSCLCs harboring a dependence on the FOXA1/GR growth program and provide rationale for its therapeutic targeting. Significance: NSCLC is the leading cause of cancer deaths worldwide. There is a need to identify novel druggable dependencies. We identify a subset of NSCLCs dependent on FOXA1-GR and sensitive to GR antagonism.
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Carcinoma de Pulmón de Células no Pequeñas , Factor Nuclear 3-alfa del Hepatocito , Neoplasias Pulmonares , Receptores de Glucocorticoides , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Factor de Crecimiento Epidérmico , Neoplasias Pulmonares/tratamiento farmacológico , Receptores de Glucocorticoides/genética , Factor Nuclear 3-alfa del Hepatocito/genéticaRESUMEN
ESR1 (estrogen receptor 1) hotspot mutations are major contributors to therapeutic resistance in estrogen receptor-positive (ER+) breast cancer. Such mutations confer estrogen independence to ERα, providing a selective advantage in the presence of estrogen-depleting aromatase inhibitors. In addition, ESR1 mutations reduce the potency of tamoxifen and fulvestrant, therapies that bind ERα directly. These limitations, together with additional liabilities, inspired the development of the next generation of ERα-targeted therapeutics, of which giredestrant is a high-potential candidate. Here, we generated Esr1 mutant-expressing mammary gland models and leveraged patient-derived xenografts (PDXs) to investigate the biological properties of the ESR1 mutations and their sensitivity to giredestrant in vivo. In the mouse mammary gland, Esr1 mutations promote hypersensitivity to progesterone, triggering pregnancy-like tissue remodeling and profoundly elevated proliferation. These effects were driven by an altered progesterone transcriptional response and underpinned by gained sites of ERα-PR (progesterone receptor) cobinding at the promoter regions of pro-proliferation genes. PDX experiments showed that the mutant ERα-PR proliferative program is also relevant in human cancer cells. Giredestrant suppressed the mutant ERα-PR proliferation in the mammary gland more so than the standard-of-care agents, tamoxifen and fulvestrant. Giredestrant was also efficacious against the progesterone-stimulated growth of ESR1 mutant PDX models. In addition, giredestrant demonstrated activity against a molecularly characterized ESR1 mutant tumor from a patient enrolled in a phase 1 clinical trial. Together, these data suggest that mutant ERα can collaborate with PR to drive protumorigenic proliferation but remain sensitive to inhibition by giredestrant.
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Neoplasias de la Mama , Receptor alfa de Estrógeno , Animales , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carbolinas , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Estrógenos , Femenino , Fulvestrant/farmacología , Fulvestrant/uso terapéutico , Humanos , Ratones , Mutación/genética , Progesterona/farmacología , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , Receptores de Progesterona/uso terapéutico , Tamoxifeno/farmacología , Tamoxifeno/uso terapéuticoRESUMEN
Most colorectal (CRC) tumors are dependent on EGFR/KRAS/BRAF/MAPK signaling activation. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated CRC tumors. Here we show that anti-EGFR but not anti-VEGF treatment enriches for emerging ARID1A mutations in CRC patients. In addition, we find that patients with ARID1A mutations, at baseline, are associated with worse outcome when treated with cetuximab- but not bevacizumab-containing therapies; thus, this suggests that ARID1A mutations may provide both an acquired and intrinsic mechanism of resistance to anti-EGFR therapies. We find that, ARID1A and EGFR-pathway genetic alterations are mutually exclusive across lung and colorectal cancers, further supporting a functional connection between these pathways. Our results not only suggest that ARID1A could be potentially used as a predictive biomarker for cetuximab treatment decisions but also provide a rationale for exploring therapeutic MAPK inhibition in an unexpected but genetically defined segment of CRC patients.
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Antineoplásicos Inmunológicos , Cetuximab , Neoplasias Colorrectales , Proteínas de Unión al ADN , Resistencia a Antineoplásicos , Factores de Transcripción , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Cetuximab/efectos adversos , Cetuximab/farmacología , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos/genética , Humanos , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Factores de Transcripción/genéticaRESUMEN
Lung development, integrity and repair rely on precise Wnt signaling, which is corrupted in diverse diseases, including cancer. Here, we discover that EHMT2 methyltransferase regulates Wnt signaling in the lung by controlling the transcriptional activity of chromatin-bound ß-catenin, through a non-histone substrate in mouse lung. Inhibition of EHMT2 induces transcriptional, morphologic, and molecular changes consistent with alveolar type 2 (AT2) lineage commitment. Mechanistically, EHMT2 activity functions to support regenerative properties of KrasG12D tumors and normal AT2 cells-the predominant cell of origin of this cancer. Consequently, EHMT2 inhibition prevents KrasG12D lung adenocarcinoma (LUAD) tumor formation and propagation and disrupts normal AT2 cell differentiation. Consistent with these findings, low gene EHMT2 expression in human LUAD correlates with enhanced AT2 gene expression and improved prognosis. These data reveal EHMT2 as a critical regulator of Wnt signaling, implicating Ehmt2 as a potential target in lung cancer and other AT2-mediated lung pathologies.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Animales , Genes ras , Antígenos de Histocompatibilidad/genética , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metiltransferasas/metabolismo , Ratones , Proteínas Proto-Oncogénicas p21(ras)/metabolismoRESUMEN
The AKT kinases have emerged as promising therapeutic targets in oncology and both allosteric and ATP-competitive AKT inhibitors have entered clinical investigation. However, long-term efficacy of such inhibitors will likely be challenged by the development of resistance. We have established prostate cancer models of acquired resistance to the allosteric inhibitor MK-2206 or the ATP-competitive inhibitor ipatasertib following prolonged exposure. While alterations in AKT are associated with acquired resistance to MK-2206, ipatasertib resistance is driven by rewired compensatory activity of parallel signaling pathways. Importantly, MK-2206 resistance can be overcome by treatment with ipatasertib, while ipatasertib resistance can be reversed by co-treatment with inhibitors of pathways including PIM signaling. These findings demonstrate that distinct resistance mechanisms arise to the two classes of AKT inhibitors and that combination approaches may reverse resistance to ATP-competitive inhibition.
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Antineoplásicos , Proteínas Proto-Oncogénicas c-akt , Adenosina Trifosfato/farmacología , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Humanos , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with a 5% 5-year survival rate for metastatic disease, yet with limited therapeutic advancements due to insufficient understanding of and inability to accurately capture high-risk CRC patients who are most likely to recur. We aimed to improve high-risk classification by identifying biological pathways associated with outcome in adjuvant stage II/III CRC. METHODS AND FINDINGS: We included 1062 patients with stage III or high-risk stage II colon carcinoma from the prospective three-arm randomized phase 3 AVANT trial, and performed expression profiling to identify a prognostic signature. Data from validation cohort GSE39582, The Cancer Genome Atlas, and cell lines were used to further validate the prognostic biology. Our retrospective analysis of the adjuvant AVANT trial uncovered a prognostic signature capturing three biological functions-stromal, proliferative and immune-that outperformed the Consensus Molecular Subtypes (CMS) and recurrence prediction signatures like Oncotype Dx in an independent cohort. Importantly, within the immune component, high granzyme B (GZMB) expression had a significant prognostic impact while other individual T-effector genes were less or not prognostic. In addition, we found GZMB to be endogenously expressed in CMS2 tumor cells and to be prognostic in a T cell independent fashion. A limitation of our study is that these results, although robust and derived from a large dataset, still need to be clinically validated in a prospective study. CONCLUSIONS: This work furthers our understanding of the underlying biology that propagates stage II/III CRC disease progression and provides scientific rationale for future high-risk stratification and targeted treatment evaluation in biomarker defined subpopulations of resectable high-risk CRC. Our results also shed light on an alternative GZMB source with context-specific implications on the disease's unique biology.
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Neoplasias Colorrectales/metabolismo , Granzimas/fisiología , Transcriptoma , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Análisis por Conglomerados , Neoplasias Colorrectales/mortalidad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Granzimas/química , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Estudios Retrospectivos , Riesgo , Linfocitos T/metabolismo , Resultado del TratamientoRESUMEN
Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning these tumor immune phenotypes remain elusive. Here, we provide a high-resolution dissection of the entire tumor ecosystem through single-cell RNA-sequencing analysis of 15 ovarian tumors. Immune-desert tumors are characterized by unique tumor cell-intrinsic features, including metabolic pathways and low antigen presentation, and an enrichment of monocytes and immature macrophages. Immune-infiltrated and -excluded tumors differ markedly in their T cell composition and fibroblast subsets. Furthermore, our study reveals chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumor cell-T cell cross talk via CXCL16-CXCR6 and stromal-immune cell cross talk via CXCL12/14-CXCR4. Our data highlight potential molecular mechanisms that shape the tumor immune phenotypes and may inform therapeutic strategies to improve clinical benefit from cancer immunotherapies.
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Biomarcadores de Tumor/genética , Fibroblastos/inmunología , Neoplasias Ováricas/inmunología , Análisis de la Célula Individual/métodos , Células del Estroma/inmunología , Linfocitos T/inmunología , Microambiente Tumoral , Biomarcadores de Tumor/inmunología , Quimiocina CXCL12/genética , Quimiocina CXCL12/inmunología , Quimiocina CXCL16/genética , Quimiocina CXCL16/inmunología , Quimiocinas CXC/genética , Quimiocinas CXC/inmunología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , RNA-Seq , Receptores CXCR4/genética , Receptores CXCR4/inmunología , Receptores CXCR6/genética , Receptores CXCR6/inmunología , Células del Estroma/metabolismo , Células del Estroma/patología , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
PURPOSE: Lung adenocarcinomas comprise the largest fraction of non-small cell lung cancer, which is the leading cause of cancer-related deaths. Seventy-five percent of adenocarcinomas lack targeted therapies because of scarcity of druggable drivers. Here, we classified tumors on the basis of signaling similarities and discovered subgroups within this unmet patient population. EXPERIMENTAL DESIGN: We leveraged transcriptional data from >800 early- and advanced-stage patients. RESULTS: We identified three robust subtypes dubbed mucinous, proliferative, and mesenchymal with respective pathway phenotypes. These transcriptional states lack discrete and causative mutational etiology as evidenced by similarly distributed oncogenic drivers, including KRAS and EGFR. The subtypes capture heterogeneity even among tumors lacking known oncogenic drivers. Paired multi-regional intratumoral biopsies demonstrated unified subtypes despite divergently evolved prooncogenic mutations, indicating subtype stability during selective pressure. Heterogeneity among in vitro and in vivo preclinical models is expounded by the human lung adenocarcinoma subtypes and can be leveraged to discover subtype-specific vulnerabilities. As proof of concept, we identified differential subtype response to MEK pathway inhibition in a chemical library screen of 89 lung cancer cell lines, which reproduces across model systems and a clinical trial. CONCLUSIONS: Our findings support forward translational relevance of transcriptional subtypes, where further exploration therein may improve lung adenocarcinoma treatment.See related commentary by Skoulidis, p. 913.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Biomarcadores de Tumor/genética , Neoplasias Pulmonares/tratamiento farmacológico , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Animales , Línea Celular Tumoral , Ensayos Clínicos como Asunto , Conjuntos de Datos como Asunto , Femenino , Heterogeneidad Genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Ratones , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/farmacología , RNA-Seq , Transcriptoma/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in a quarter of patients with lung adenocarcinoma and a third of patients with lung squamous cell carcinoma. In lung adenocarcinoma, KEAP1 loss often co-occurs with STK11 loss and KRAS-activating alterations. Despite its prevalence, the impact of NRF2 activation on tumor progression and patient outcomes is not fully defined. EXPERIMENTAL DESIGN: We model NRF2 activation, STK11 loss, and KRAS activation in vivo using novel genetically engineered mouse models. Furthermore, we derive a NRF2 activation signature from human non-small cell lung tumors that we use to dissect how these genomic events impact outcomes and immune contexture of participants in the OAK and IMpower131 immunotherapy trials. RESULTS: Our in vivo data reveal roles for NRF2 activation in (i) promoting rapid-onset, multifocal intrabronchiolar carcinomas, leading to lethal pulmonary dysfunction, and (ii) decreasing elevated redox stress in KRAS-mutant, STK11-null tumors. In patients with nonsquamous tumors, the NRF2 signature is negatively prognostic independently of STK11 loss. Patients with lung squamous cell carcinoma with low NRF2 signature survive longer when receiving anti-PD-L1 treatment. CONCLUSIONS: Our in vivo modeling establishes NRF2 activation as a critical oncogenic driver, cooperating with STK11 loss and KRAS activation to promote aggressive lung adenocarcinoma. In patients, oncogenic events alter the tumor immune contexture, possibly having an impact on treatment responses. Importantly, patients with NRF2-activated nonsquamous or squamous tumors have poor prognosis and show limited response to anti-PD-L1 treatment.
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Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Factor 2 Relacionado con NF-E2/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP/genética , Proteínas Quinasas Activadas por AMP/genética , Animales , Antígeno B7-H1/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Perfilación de la Expresión Génica , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estimación de Kaplan-Meier , Proteína 1 Asociada A ECH Tipo Kelch/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Ratones , Factor 2 Relacionado con NF-E2/genética , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what controls the spatial distribution of T cells in the tumour microenvironment is not well understood. Here we couple digital pathology and transcriptome analysis on a large ovarian tumour cohort and develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFß and activated stroma. Furthermore, we identify TGFß as an important mediator of T cell exclusion. TGFß reduces MHC-I expression in ovarian cancer cells in vitro. TGFß also activates fibroblasts and induces extracellular matrix production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFß might be a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.
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Linfocitos T CD8-positivos/inmunología , Carcinoma Epitelial de Ovario/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Neoplasias Ováricas/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Microambiente Tumoral/inmunología , Presentación de Antígeno/inmunología , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Estudios de Cohortes , Metilación de ADN , Endopeptidasas , Femenino , Gelatinasas/metabolismo , Perfilación de la Expresión Génica , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Aprendizaje Automático , Proteínas de la Membrana/metabolismo , Familia de Multigenes , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Pronóstico , RNA-Seq , Serina Endopeptidasas/metabolismo , Células del Estroma/metabolismoRESUMEN
BACKGROUND: We aimed to develop a gene expression-based prognostic signature for isocitrate dehydrogenase (IDH) wild-type glioblastoma using clinical trial datasets representative of glioblastoma clinical trial populations. METHODS: Samples were collected from newly diagnosed patients with IDH wild-type glioblastoma in the ARTE, TAMIGA, EORTC 26101 (referred to as "ATE"), AVAglio, and GLARIUS trials, or treated at UCLA. Transcriptional profiling was achieved with the NanoString gene expression platform. To identify genes prognostic for overall survival (OS), we built an elastic net penalized Cox proportional hazards regression model using the discovery ATE dataset. For validation in independent datasets (AVAglio, GLARIUS, UCLA), we combined elastic net-selected genes into a robust z-score signature (ATE score) to overcome gene expression platform differences between discovery and validation cohorts. RESULTS: NanoString data were available from 512 patients in the ATE dataset. Elastic net identified a prognostic signature of 9 genes (CHEK1, GPR17, IGF2BP3, MGMT, MTHFD1L, PTRH2, SOX11, S100A9, and TFRC). Translating weighted elastic net scores to the ATE score conserved the prognostic value of the genes. The ATE score was prognostic for OS in the ATE dataset (Pâ <â 0.0001), as expected, and in the validation cohorts (AVAglio, Pâ <â 0.0001; GLARIUS, Pâ =â 0.02; UCLA, Pâ =â 0.004). The ATE score remained prognostic following adjustment for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and corticosteroid use at baseline. A positive correlation between ATE score and proneural/proliferative subtypes was observed in patients with MGMT non-methylated promoter status. CONCLUSIONS: The ATE score showed prognostic value and may enable clinical trial stratification for IDH wild-type glioblastoma.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/genética , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Glioblastoma/genética , Humanos , Isocitrato Deshidrogenasa/genética , Pronóstico , Receptores Acoplados a Proteínas GRESUMEN
BACKGROUND: Metastatic breast cancer is the leading cause of cancer death in women, but the genomics of metastasis in breast cancer are poorly studied. METHODS: We explored a set of 11,616 breast tumors, including 5,034 metastases, which had undergone targeted sequencing during standard clinical care. RESULTS: Besides the known hotspot mutations in ESR1, we observed a metastatic enrichment of previously unreported, lower-prevalence mutations in the ligand-binding domain, implying that these mutations may also be functional. Furthermore, individual ESR1 hotspots are significantly enriched in specific metastatic tissues and histologies, suggesting functional differences between these mutations. Other alterations enriched across all metastases include loss of function of the CDK4 regulator CDKN1B, and mutations in the transcription factor CTCF. Mutations enriched at specific metastatic sites generally reflect biology of the target tissue and may be adaptations to growth in the local environment. These include PTEN and ASXL1 alterations in brain metastases and NOTCH1 alterations in skin. We observed an enrichment of KRAS, KEAP1, STK11 and EGFR mutations in lung metastases. However, the patterns of other mutations in these tumors indicate that these are misdiagnosed lung primaries rather than breast metastases. CONCLUSIONS: An order-of-magnitude increase in samples relative to previous studies allowed us to detect novel genomic characteristics of metastatic cancer and to expand and clarify previous findings.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Adulto , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , Receptor alfa de Estrógeno/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Genes erbB-2 , Genómica , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Metástasis Linfática , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , PrevalenciaRESUMEN
Estrogen receptor-positive (ER+) breast cancers frequently remain dependent on ER signaling even after acquiring resistance to endocrine agents, prompting the development of optimized ER antagonists. Fulvestrant is unique among approved ER therapeutics due to its capacity for full ER antagonism, thought to be achieved through ER degradation. The clinical potential of fulvestrant is limited by poor physicochemical features, spurring attempts to generate ER degraders with improved drug-like properties. We show that optimization of ER degradation does not guarantee full ER antagonism in breast cancer cells; ER "degraders" exhibit a spectrum of transcriptional activities and anti-proliferative potential. Mechanistically, we find that fulvestrant-like antagonists suppress ER transcriptional activity not by ER elimination, but by markedly slowing the intra-nuclear mobility of ER. Increased ER turnover occurs as a consequence of ER immobilization. These findings provide proof-of-concept that small molecule perturbation of transcription factor mobility may enable therapeutic targeting of this challenging target class.
Asunto(s)
Neoplasias de la Mama/metabolismo , Antagonistas del Receptor de Estrógeno/farmacología , Fulvestrant/farmacología , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/metabolismo , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Cinamatos/farmacología , Resistencia a Antineoplásicos , Antagonistas del Receptor de Estrógeno/uso terapéutico , Femenino , Fulvestrant/uso terapéutico , Células HEK293 , Xenoinjertos , Humanos , Indazoles/farmacología , Ligandos , Células MCF-7 , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Polimorfismo de Nucleótido Simple , Proteolisis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacosRESUMEN
The lack of predictive preclinical models is a fundamental barrier to translating knowledge about the molecular pathogenesis of cancer into improved therapies. Insertional mutagenesis (IM) in mice is a robust strategy for generating malignancies that recapitulate the extensive inter- and intra-tumoral genetic heterogeneity found in advanced human cancers. While the central role of "driver" viral insertions in IM models that aberrantly increase the expression of proto-oncogenes or disrupt tumor suppressors has been appreciated for many years, the contributions of cooperating somatic mutations and large chromosomal alterations to tumorigenesis are largely unknown. Integrated genomic studies of T lineage acute lymphoblastic leukemias (T-ALLs) generated by IM in wild-type (WT) and Kras mutant mice reveal frequent point mutations and other recurrent non-insertional genetic alterations that also occur in human T-ALL. These somatic mutations are sensitive and specific markers for defining clonal dynamics and identifying candidate resistance mechanisms in leukemias that relapse after an initial therapeutic response. Primary cancers initiated by IM and resistant clones that emerge during in vivo treatment close key gaps in existing preclinical models, and are robust platforms for investigating the efficacy of new therapies and for elucidating how drug exposure shapes tumor evolution and patterns of resistance.
Asunto(s)
Genómica , Leucemia-Linfoma Linfoblástico de Células T Precursoras/dietoterapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Línea Celular Tumoral , Aberraciones Cromosómicas , Evolución Clonal/genética , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Humanos , Ratones , Mutagénesis Insercional/genética , Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologíaRESUMEN
Cellular senescence is a tumor suppressive mechanism that can paradoxically contribute to aging pathologies. Despite evidence of immune clearance in mouse models, it is not known how senescent cells (SnCs) persist and accumulate with age or in tumors in individuals. Here, we identify cooperative mechanisms that orchestrate the immunoevasion and persistence of normal and cancer human SnCs through extracellular targeting of natural killer receptor signaling. Damaged SnCs avoid immune recognition through MMPs-dependent shedding of NKG2D-ligands reinforced via paracrine suppression of NKG2D receptor-mediated immunosurveillance. These coordinated immunoediting processes are evident in residual, drug-resistant tumors from cohorts of >700 prostate and breast cancer patients treated with senescence-inducing genotoxic chemotherapies. Unlike in mice, these reversible senescence-subversion mechanisms are independent of p53/p16 and exacerbated in oncogenic RAS-induced senescence. Critically, the p16INK4A tumor suppressor can disengage the senescence growth arrest from the damage-associated immune senescence program, which is manifest in benign nevi lesions where indolent SnCs accumulate over time and preserve a non-pro-inflammatory tissue microenvironment maintaining NKG2D-mediated immunosurveillance. Our study shows how subpopulations of SnCs elude immunosurveillance, and reveals secretome-targeted therapeutic strategies to selectively eliminate -and restore the clearance of- the detrimental SnCs that actively persist after chemotherapy and accumulate at sites of aging pathologies.
Asunto(s)
Envejecimiento/inmunología , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Senescencia Celular/inmunología , Resistencia a Antineoplásicos/inmunología , Neoplasias de la Próstata/tratamiento farmacológico , Escape del Tumor/inmunología , Envejecimiento/patología , Animales , Antineoplásicos/uso terapéutico , Biopsia , Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Daño del ADN/efectos de los fármacos , Conjuntos de Datos como Asunto , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Vigilancia Inmunológica/efectos de los fármacos , Vigilancia Inmunológica/inmunología , Masculino , Metaloendopeptidasas/metabolismo , Ratones , Subfamilia K de Receptores Similares a Lectina de Células NK/antagonistas & inhibidores , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Próstata/patología , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Análisis de Matrices Tisulares , Escape del Tumor/efectos de los fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Perfilación de la Expresión Génica/métodos , Genómica/métodos , Receptor ErbB-2/genética , Neoplasias de la Mama Triple Negativas/clasificación , Pueblo Asiatico/genética , Biomarcadores de Tumor/genética , Cromosomas Humanos Par 22/genética , Variaciones en el Número de Copia de ADN , Femenino , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Mutación , Metástasis de la Neoplasia , Pronóstico , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
The identification of early breast cancer patients who may benefit from adjuvant chemotherapy has evolved to include assessment of clinicopathologic features such as tumor size and nodal status, as well as several gene-expression profiles for ER-positive, HER2-negative cancers. However, these tools do not reliably identify patients at the greatest risk of recurrence. The mutation and copy-number landscape of triple-negative breast cancer (TNBC) subtypes defined by gene expression is also largely unknown, and elucidation of this landscape may shed light on novel therapeutic opportunities. The USO01062 phase III clinical trial of standard chemotherapy (with or without capecitabine) enrolled a cohort of putatively high-risk patients based on clinical features, yet only observed a 5-year disease-free survival event rate of 11.6%. In order to uncover genomic aberrations associated with recurrence, a targeted next-generation sequencing panel was used to compare tumor specimens from patients who had a recurrence event with a matched set who did not. The somatic mutation and copy-number alteration landscapes of high-risk early breast cancer patients were characterized and alterations associated with relapse were identified. Tumor mutational burden was evaluated but was not prognostic in this study, nor did it correlate with PDL1 or CD8 gene expression. However, TNBC subtypes had substantial genomic heterogeneity with a distinct pattern of genomic alterations and putative underlying driver mutations. IMPLICATIONS: The present study uncovers a compendium of genomic alterations with utility to more precisely identify high-risk patients for adjuvant trials of novel therapeutic agents.