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Controlling large-scale many-body quantum systems at the level of single photons and single atomic systems is a central goal in quantum information science and technology. Intensive research and development has propelled foundry-based silicon-on-insulator photonic integrated circuits to a leading platform for large-scale optical control with individual mode programmability. However, integrating atomic quantum systems with single-emitter tunability remains an open challenge. Here, we overcome this barrier through the hybrid integration of multiple InAs/InP microchiplets containing high-brightness infrared semiconductor quantum dot single photon emitters into advanced silicon-on-insulator photonic integrated circuits fabricated in a 300 mm foundry process. With this platform, we achieve single-photon emission via resonance fluorescence and scalable emission wavelength tunability. The combined control of photonic and quantum systems opens the door to programmable quantum information processors manufactured in leading semiconductor foundries.
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People often modify the shoreline to mitigate erosion and protect property from storm impacts. The 2 main approaches to modification are gray infrastructure (e.g., bulkheads and seawalls) and natural or green infrastructure (NI) (e.g., living shorelines). Gray infrastructure is still more often used for coastal protection than NI, despite having more detrimental effects on ecosystem parameters, such as biodiversity. We assessed the impact of gray infrastructure on biodiversity and whether the adoption of NI can mitigate its loss. We examined the literature to quantify the relationship of gray infrastructure and NI to biodiversity and developed a model with temporal geospatial data on ecosystem distribution and shoreline modification to project future shoreline modification for our study location, coastal Georgia (United States). We applied the literature-derived empirical relationships of infrastructure effects on biodiversity to the shoreline modification projections to predict change in biodiversity under different NI versus gray infrastructure scenarios. For our study area, which is dominated by marshes and use of gray infrastructure, when just under half of all new coastal infrastructure was to be NI, previous losses of biodiversity from gray infrastructure could be mitigated by 2100 (net change of biodiversity of +0.14%, 95% confidence interval -0.10% to +0.39%). As biodiversity continues to decline from human impacts, it is increasingly imperative to minimize negative impacts when possible. We therefore suggest policy and the permitting process be changed to promote the adoption of NI.
Cuantificación del impacto de la futura modificación de la costa sobre la biodiversidad en un estudio de caso de la costa de Georgia, Estados Unidos Resumen Las personas modifican con frecuencia la costa para mitigar la erosión o proteger su propiedad del impacto de las tormentas. Los dos enfoques principales para la modificación son la infraestructura gris (p. ej.: mamparos y malecones) y la infraestructura verde o natural (IN) (p.ej.: costas vivientes). La infraestructura gris es más común que la IN, a pesar de que tiene efectos dañinos sobre los parámetros ambientales, como la biodiversidad. Evaluamos el impacto de la infraestructura gris sobre la biodiversidad y si la adopción de la IN puede mitigar su pérdida. Analizamos la literatura para cuantificar la relación de la infraestructura gris y la IN con la biodiversidad. También desarrollamos un modelo con datos geoespaciales temporales sobre la distribución de los ecosistemas y la modificación de la costa para proyectar la modificación costera en el futuro en nuestra localidad de estudio: la costa de Georgia, Estados Unidos. Aplicamos las relaciones empíricas derivadas de la literatura de los efectos de la infraestructura sobre la biodiversidad a las proyecciones de modificación de la costa para predecir el cambio en la biodiversidad bajo diferentes escenarios de infraestructura gris versus IN. En nuestra área de estudio, que está dominada por marismas y usa infraestructura gris, cuando un poco menos de la mitad de toda la infraestructura costera nueva debería ser IN, las pérdidas previas de biodiversidad a partir de la infraestructura gris podrían mitigarse para 2100 (cambio neto de la biodiversidad de +0.14%, 95% intervalo de confianza 0.10% a +0.39%). Conforme la biodiversidad siga en declive por el impacto humano, cada vez es más imperativo minimizar el impacto negativo cuando sea posible. Por lo tanto, sugerimos que se modifiquen las políticas y el proceso de permisos para promover la adopción de la IN.
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AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier.
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Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.
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Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutação , Células-Tronco/metabolismo , Células-Tronco Neoplásicas/metabolismoRESUMO
Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.
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Redes Reguladoras de Genes , Leucemia Mieloide Aguda , Humanos , Regulon , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutação/genética , RNA Interferente Pequeno , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Sea level rise (SLR) is the most significant climate change-related threat to coastal wetlands, driving major transformations in coastal regions through marsh migration. Landscape transformations due to marsh migration are manifested in terms of horizontal and vertical changes in land cover and elevation, respectively. These processes will have an impact on saltmarsh wave attenuation that is yet to be explored. This study stands as a comprehensive analysis of spatially distributed wave attenuation by vegetation in the context of a changing climate. Our results show that: i) changes in saltmarsh cover have little to no effect on the attenuation of floods, while ii) changes in elevation can significantly reduce flood extents and water depths; iii) overland wave heights are directly influenced by marsh migration, although iv) being indirectly attenuated by the water depth limiting effects of water depth attenuation driven by changes in elevation; v) the influence of saltmarsh accretion on wave attenuation is largely evident near the marsh edge, where the increasing elevations can drive major wave energy losses via wave breaking. Lastly, vi) considering the synergy between SLR, marsh migration, and changes in elevation results in significantly more wave attenuation than considering the eustatic effects of SLR and/or horizontal marsh migration alone, and therefore should be adopted in future studies.
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Elevação do Nível do Mar , Áreas Alagadas , Monitoramento Ambiental , Mudança Climática , Água , EcossistemaRESUMO
Coastal communities are vulnerable to wave and storm surges during extreme events, highlighting the need to increase community resilience. The effectiveness of natural wetlands in attenuating waves is vital to designing strategies for protecting public safety. This study aimed to understand how vegetation attenuates waves and determine the best method for modeling vegetation's impact on wave dynamics. The researchers compared two different vegetation representations in numerical models, implicit and explicit, using SWAN and XBeach at varying spatial resolutions. The study focused on two marshes in the Chesapeake Bay, using field measurements to investigate the accuracy of each method in representing wave attenuation by vegetation and the implications of explicitly representing average characteristics of one vegetation species on a regional level. Results showed that explicit modeling using average vegetation characteristics provided more accurate results than the implicit model, which only showed wave attenuation due to topography. The finer scale resolution and site-specific vegetation characteristics further improved the accuracy of wave attenuation observed. Understanding the trade-offs between different vegetation representations in numerical models is essential to accurately represent wave attenuation and design effective protection strategies for coastal communities.
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Baías , Monitoramento Ambiental , Áreas AlagadasRESUMO
AML is a heterogenous disease caused by different mutations. We have previously shown that each mutational sub-type develops its specific gene regulatory network (GRN) with transcription factors interacting with multiple gene modules, many of which are transcription factor genes themselves. Here we hypothesized that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We tested this hypothesis using FLT3-ITD mutated AML as a model and conducted an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict identifying crucial regulatory modules required for AML but not normal cellular growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD AML and that its removal leads to GRN collapse and cell death.
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Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combined LSD1 and FLT3 inhibition induces synergistic cell death in FLT3-mutant AML. Multi-omic profiling revealed that the drug combination disrupts STAT5, LSD1, and GFI1 binding at the MYC blood superenhancer, suppressing superenhancer accessibility as well as MYC expression and activity. The drug combination simultaneously results in the accumulation of repressive H3K9me1 methylation, an LSD1 substrate, at MYC target genes. We validated these findings in 72 primary AML samples with the nearly every sample demonstrating synergistic responses to the drug combination. Collectively, these studies reveal how epigenetic therapies augment the activity of kinase inhibitors in FLT3-ITD (internal tandem duplication) AML. IMPLICATIONS: This work establishes the synergistic efficacy of combined FLT3 and LSD1 inhibition in FLT3-ITD AML by disrupting STAT5 and GFI1 binding at the MYC blood-specific superenhancer complex.
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Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Humanos , Apoptose , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fator de Transcrição STAT5/metabolismoRESUMO
Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. However, the role of ASXL1 in myeloid lineage maturation is incompletely described. To define the role of ASXL1 in myelopoiesis, we employed single cell RNA sequencing and a murine model of hematopoietic-specific Asxl1 deletion. In granulocyte progenitors, Asxl1 deletion leads to hyperactivation of MYC and a quantitative decrease in neutrophil production. This loss of granulocyte production was not accompanied by significant changes in the landscape of covalent histone modifications. However, Asxl1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription. These results suggest that ASXL1 inhibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator in myeloid development.
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Síndromes Mielodisplásicas , RNA Polimerase II , Proteínas Repressoras , Animais , Humanos , Camundongos , Células Precursoras de Granulócitos/patologia , Mutação , Síndromes Mielodisplásicas/genética , Proteínas Repressoras/genética , RNA Polimerase II/genética , Fatores de Transcrição/genéticaRESUMO
Genome-wide mapping of histone modifications is critical to understanding transcriptional regulation. CUT&Tag is a new method for profiling histone modifications, offering improved sensitivity and decreased cost compared with ChIP-seq. Here, we present GoPeaks, a peak calling method specifically designed for histone modification CUT&Tag data. We compare the performance of GoPeaks against commonly used peak calling algorithms to detect histone modifications that display a range of peak profiles and are frequently used in epigenetic studies. We find that GoPeaks robustly detects genome-wide histone modifications and, notably, identifies a substantial number of H3K27ac peaks with improved sensitivity compared to other standard algorithms.
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Código das Histonas , Processamento de Proteína Pós-Traducional , Imunoprecipitação da Cromatina/métodos , Genoma , Análise de Sequência de DNA/métodosRESUMO
Responses to kinase-inhibitor therapy in AML are frequently short-lived due to the rapid development of resistance, limiting the clinical efficacy. Combination therapy may improve initial therapeutic responses by targeting pathways used by leukemia cells to escape monotherapy. Here we report that combined inhibition of KIT and lysine-specific demethylase 1 (LSD1) produces synergistic cell death in KIT-mutant AML cell lines and primary patient samples. This drug combination evicts both MYC and PU.1 from chromatin driving cell cycle exit. Using a live cell biosensor for AKT activity, we identify early adaptive changes in kinase signaling following KIT inhibition that are reversed with the addition of LSD1 inhibitor via modulation of the GSK3a/b axis. Multi-omic analyses, including scRNA-seq, ATAC-seq and CUT&Tag, confirm these mechanisms in primary KIT-mutant AML. Collectively, this work provides rational for a clinical trial to assess the efficacy of KIT and LSD1 inhibition in patients with KIT-mutant AML.
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Histona Desmetilases , Leucemia Mieloide Aguda , Ciclo Celular , Linhagem Celular Tumoral , Redes Reguladoras de Genes , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismoRESUMO
The transcription factor RUNX1 is essential for correct hematopoietic development; in its absence in the germ line, blood stem cells are not formed. RUNX1 orchestrates dramatic changes in the chromatin landscape at the onset of stem cell formation, which set the stage for both stem self-renewal and further differentiation. However, once blood stem cells are formed, the mutation of the RUNX1 gene is not lethal but can lead to various hematopoietic defects and a predisposition to cancer. Here we summarize the current literature on inherited and acquired RUNX1 mutations, with a particular emphasis on mutations that alter the structure of the RUNX1 protein itself, and place these changes in the context of what is known about RUNX1 function. We also summarize which mutant RUNX1 proteins are actually expressed in cells and discuss the molecular mechanism underlying how such variants reprogram the epigenome setting stem cells on the path to malignancy.
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Subunidade alfa 2 de Fator de Ligação ao Core , Doenças Hematológicas , Cromatina/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Doenças Hematológicas/genética , Hematopoese/genética , Humanos , MutaçãoRESUMO
T cell immunological memory is established within days of an infection, but little is known about the in vivo changes in gene regulatory networks accounting for their ability to respond more efficiently to secondary infections. To decipher the timing and nature of immunological memory we performed genome-wide analyses of epigenetic and transcriptional changes in a mouse model generating antigen-specific T cells. Epigenetic reprogramming for Th differentiation and memory T cell formation was already established by the peak of the T cell response after 7 days. The Th memory T cell program was associated with a gain of open chromatin regions, enriched for RUNX, ETS and T-bet motifs, which remained stable for 56 days. The epigenetic programs for both effector memory, associated with T-bet, and central memory, associated with TCF-1, were established in parallel. Memory T cell-specific regulatory elements were associated with greatly enhanced inducible Th1-biased responses during secondary exposures to antigen. Furthermore, memory T cells responded in vivo to re-exposure to antigen by rapidly reprograming the entire ETS factor gene regulatory network, by suppressing Ets1 and activating Etv6 expression. These data show that gene regulatory networks are epigenetically reprogrammed towards memory during infection, and undergo substantial changes upon re-stimulation.
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Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Epigênese Genética , Redes Reguladoras de Genes , Memória Imunológica , Animais , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Fatores de TempoRESUMO
PURPOSE: Lineage plasticity in prostate cancer-most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program-is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC. Moreover, the incidence of treatment-emergent NEPC (t-NEPC) is increasing in the era of novel AR inhibitors. In contradistinction to de novo NEPC, t-NEPC tumors often express the AR, but AR's functional role in t-NEPC is unknown. Furthermore, targetable factors that promote t-NEPC lineage plasticity are also unclear. EXPERIMENTAL DESIGN: Using an integrative systems biology approach, we investigated enzalutamide-resistant t-NEPC cell lines and their parental, enzalutamide-sensitive adenocarcinoma cell lines. The AR is still expressed in these t-NEPC cells, enabling us to determine the role of the AR and other key factors in regulating t-NEPC lineage plasticity. RESULTS: AR inhibition accentuates lineage plasticity in t-NEPC cells-an effect not observed in parental, enzalutamide-sensitive adenocarcinoma cells. Induction of an AR-repressed, lineage plasticity program is dependent on activation of the transcription factor E2F1 in concert with the BET bromodomain chromatin reader BRD4. BET inhibition (BETi) blocks this E2F1/BRD4-regulated program and decreases growth of t-NEPC tumor models and a subset of t-NEPC patient tumors with high activity of this program in a BETi clinical trial. CONCLUSIONS: E2F1 and BRD4 are critical for activating an AR-repressed, t-NEPC lineage plasticity program. BETi is a promising approach to block this program.
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Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Fator de Transcrição E2F1/efeitos dos fármacos , Fator de Transcrição E2F1/fisiologia , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Proteínas/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , MasculinoRESUMO
Neuroendocrine prostate cancer (NEPC) is the most virulent form of prostate cancer. Importantly, our recent work examining metastatic biopsy samples demonstrates NEPC is increasing in frequency. In contrast to prostate adenocarcinomas that express a luminal gene expression program, NEPC tumors express a neuronal gene expression program. Despite this distinction, the diagnosis of NEPC is often challenging, demonstrating an urgent need to identify new biomarkers and therapeutic targets. Our prior work demonstrated that the histone demethylase LSD1 (KDM1A) is important for survival of prostate adenocarcinomas, but little was known about LSD1's role in NEPC. Recently, a neural-specific transcript variant of LSD1-LSD1+8a-was discovered and demonstrated to activate neuronal gene expression in neural cells. The splicing factor SRRM4 was previously shown to promote LSD1+8a splicing in neuronal cells, and SRRM4 promotes NEPC differentiation and cell survival. Therefore, we sought to determine if LSD1+8a might play a role in NEPC and whether LSD1+8a splicing was linked to SRRM4. To investigate a potential role for LSD1+8a in NEPC, we examined a panel of prostate adenocarcinoma and NEPC patient-derived xenografts and metastatic biopsies. LSD1+8a was expressed exclusively in NEPC samples and correlated significantly with elevated expression of SRRM4. Using SRRM4-overexpressing cell lines, we determined that SRRM4 mediates alternative splicing of LSD1+8a. Finally, using gain of function studies, we confirmed that LSD1+8a and SRRM4 co-regulate target genes distinct from canonical LSD1. Our findings suggest further study of the interplay between SRRM4 and LSD1+8a and mechanisms by which LSD1+8a regulates gene expression in NEPC is warranted.
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Histona Desmetilases/genética , Proteínas do Tecido Nervoso/genética , Tumores Neuroendócrinos/genética , Neoplasias da Próstata/genética , Processamento Alternativo/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Epigenômica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Tumores Neuroendócrinos/patologiaRESUMO
Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.
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Proteínas Estimuladoras de Ligação a CCAAT/genética , Inibidores Enzimáticos/administração & dosagem , Histona Desmetilases/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Receptores de Fator Estimulador de Colônias/genética , Fatores de Transcrição STAT/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Feminino , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Fator Estimulador de Colônias/metabolismo , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Nearly all prostate cancers start out as adenocarcinomas driven by the androgen receptor (AR). Neuroendocrine prostate cancer (NEPC) is a rare, AR-independent subtype with a poor prognosis and limited treatment options. Importantly, because of the widespread use of novel AR-targeting agents, the incidence of treatment-emergent (t)-NEPC is increasing in frequency. Molecular features commonly found in prostate adenocarcinomas are now well-recognized, including defects in homologous recombination (HR) genes, like breast cancer type 2 susceptibility protein (BRCA2), leading to increased sensitivity to deoxyribonucleic acid (DNA)-damaging agents (e.g., platinum chemotherapy or poly adenosine diphosphate-ribose polymerase (PARP) inhibitors). However, our own prior work demonstrates that HR gene defects are uncommon in t-NEPC. Herein, we describe a patient who originally presented with adenocarcinoma but who subsequently developed t-NEPC. Molecular testing determined that his t-NEPC tumor (but not his original adenocarcinoma) harbored complete copy number loss of BRCA2, as well as copy number loss of another HR gene - ataxia telangiectasia, mutated (ATM). Uncharacteristically for t-NEPC, the patient achieved a complete response to platinum chemotherapy. Based on emerging data for the role of maintenance PARP inhibitor therapy in ovarian cancer patients whose tumors harbor BRCA1/2 defects, we treated him with PARP inhibitor maintenance after chemotherapy. At nine months follow-up, the patient was still in complete remission. This report demonstrates the importance of molecular testing to clarify the biology of exceptional responders and to direct treatment. Our results also suggest that clinical trials of PARP inhibitor maintenance may be warranted in select patients with advanced prostate cancer, including those with t-NEPC, whose tumors harbor HR defects.
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BET bromodomain inhibitors block prostate cancer cell growth at least in part through c-Myc and androgen receptor (AR) suppression. However, little is known about other transcriptional regulators whose suppression contributes to BET bromodomain inhibitor anti-tumor activity. Moreover, the anti-tumor activity of BET bromodomain inhibition in AR-independent castration-resistant prostate cancers (CRPC), whose frequency is increasing, is also unknown. Herein, we demonstrate that BET bromodomain inhibition blocks growth of a diverse set of CRPC cell models, including those that are AR-independent or in which c-Myc is not suppressed. To identify transcriptional regulators whose suppression accounts for these effects, we treated multiple CRPC cell lines with the BET bromodomain inhibitor JQ1 and then performed RNA-sequencing followed by Master Regulator computational analysis. This approach identified several previously unappreciated transcriptional regulators that are highly expressed in CRPC and whose suppression, via both transcriptional or post-translational mechanisms, contributes to the anti-tumor activity of BET bromodomain inhibitors.