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Recent advances in human genetics have shed light on the genetic factors contributing to inflammatory diseases, particularly Crohn's disease (CD), a prominent form of inflammatory bowel disease. Certain risk genes associated with CD directly influence cytokine biology and cell-specific communication networks. Current CD therapies primarily rely on anti-inflammatory drugs, which are inconsistently effective and lack strategies for promoting epithelial restoration and mucosal balance. To understand CD's underlying mechanisms, we investigated the link between CD and the FGFR1OP gene, which encodes a centrosome protein. FGFR1OP deletion in mouse intestinal epithelial cells disrupted crypt architecture, resulting in crypt loss, inflammation, and fatality. FGFR1OP insufficiency hindered epithelial resilience during colitis. FGFR1OP was crucial for preserving non-muscle myosin II activity, ensuring the integrity of the actomyosin cytoskeleton and crypt cell adhesion. This role of FGFR1OP suggests that its deficiency in genetically predisposed individuals may reduce epithelial renewal capacity, heightening susceptibility to inflammation and disease.
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Aerobic glycolysis, or the Warburg effect, is used by cancer cells for proliferation while producing lactate. Although lactate production has wide implications for cancer progression, it is not known how this effect increases cell proliferation and relates to oxidative phosphorylation. Here, we elucidate that a negative feedback loop (NFL) is responsible for the Warburg effect. Further, we show that aerobic glycolysis works as an amplifier of oxidative phosphorylation. On the other hand, quiescence is an important property of cancer stem cells. Based on the NFL, we show that both aerobic glycolysis and oxidative phosphorylation, playing a synergistic role, are required to achieve cell quiescence. Further, our results suggest that the cells in their hypoxic niche are highly proliferative yet close to attaining quiescence by increasing their NADH/NAD+ ratio through the severity of hypoxia. The findings of this study can help in a better understanding of the link among metabolism, cell cycle, carcinogenesis, and stemness.
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Proliferación Celular , Retroalimentación Fisiológica , Glucólisis , Células Madre Neoplásicas , Fosforilación Oxidativa , Efecto Warburg en Oncología , Humanos , Glucólisis/fisiología , Retroalimentación Fisiológica/fisiología , Células Madre Neoplásicas/metabolismo , Proliferación Celular/fisiología , Neoplasias/metabolismo , NAD/metabolismo , Ácido Láctico/metabolismo , Modelos Biológicos , Línea Celular Tumoral , Ciclo Celular/fisiologíaRESUMEN
Background and Aims: Regional anesthesia techniques have attributed a multimodal dimension to pain management after breast surgery. The intercostal approach to paravertebral block has been gaining interest, becoming an alternative to conventional paravertebral block, devoid of complexities in its approach, being recognized as the proximal intercostal block. Parallel to the widespread acceptance of fascial plane blocks in breast surgery, pectoralis II block has emerged as being non-inferior to paravertebral block. The aim of this study was to evaluate the efficacy of two independent fascial plane blocks, proximal intercostal block and pectoralis II block, in breast conservation surgery. Material and Methods: This prospective, randomized control, pilot study included 40 patients, randomly allocated among two groups: proximal intercostal block and pectoralis II block. Results: The pectoralis II block group had significantly lower pain scores at rest in the immediate postoperative period but became comparable with the proximal intercostal block group in the late postoperative period. Pain scores on movement though were lower at 0 h postoperatively and became comparable with the proximal intercostal block group subsequently. Although the pectoralis II group had earlier recovery in the post-anesthesia care unit, the overall time to discharge from the hospital was comparable and not influential. Both groups had high patient satisfaction scores and similar perioperative opioid consumption. Sedation, time to first rescue analgesia, and postoperative nausea vomiting scores were comparable. Conclusion: Fascial plane blocks in the form of pectoralis II and proximal intercostal block facilitate pain alleviation, early return to shoulder arm exercise, and enhanced recovery, which should render them to be incorporated into multimodal interdisciplinary pain management in breast conservation surgery.
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Effective tissue repair requires coordinated intercellular communication to sense damage, remodel the tissue, and restore function. Here, we dissected the healing response in the intestinal mucosa by mapping intercellular communication at single-cell resolution and integrating with spatial transcriptomics. We demonstrated that a risk variant for Crohn's disease, hepatocyte growth factor activator (HGFAC) Arg509His (R509H), disrupted a damage-sensing pathway connecting the coagulation cascade to growth factors that drive the differentiation of wound-associated epithelial (WAE) cells and production of a localized retinoic acid (RA) gradient to promote fibroblast-mediated tissue remodeling. Specifically, we showed that HGFAC R509H was activated by thrombin protease activity but exhibited impaired proteolytic activation of the growth factor macrophage-stimulating protein (MSP). In Hgfac R509H mice, reduced MSP activation in response to wounding of the colon resulted in impaired WAE cell induction and delayed healing. Through integration of single-cell transcriptomics and spatial transcriptomics, we demonstrated that WAE cells generated RA in a spatially restricted region of the wound site and that mucosal fibroblasts responded to this signal by producing extracellular matrix and growth factors. We further dissected this WAE cell-fibroblast signaling circuit in vitro using a genetically tractable organoid coculture model. Collectively, these studies exploited a genetic perturbation associated with human disease to disrupt a fundamental biological process and then reconstructed a spatially resolved mechanistic model of tissue healing.
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Enfermedad de Crohn , Ratones , Humanos , Animales , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Transducción de Señal , Células Epiteliales/metabolismo , Mucosa Intestinal/metabolismo , Diferenciación CelularRESUMEN
The classical role of C-terminal binding protein (CtBP) is that of a global corepressor. However, its exact mechanism of repression is not known. In this review, we elucidate the repression motif used by CtBP. Further, we provide other unifying features of its mechanism of action. For example, in the presence of a high NADH/NAD+ ratio in the cell, causing a low glycolytic condition, the NADH-bound dimeric form of CtBP causes global repression, maintaining balances and homeostases of many cellular processes, under the cell surveillance of p53 and NFkB. In contrast, in the presence of a low NADH/NAD+ ratio, causing a high glycolytic condition, the NADH-free monomeric form of CtBP blocks p53 function and NFkB-mediated transcription. Further, a low NADH/NAD+ ratio upsets the homeostases and balances in the absence of the cell surveillances of p53 and NFkB, causing global instability, the dominant outcome of CtBP's action in carcinogenesis, in cells in a high glycolytic state.
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NAD , Proteína p53 Supresora de Tumor , Humanos , NAD/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Oxidorreductasas de Alcohol/genética , Oxidorreductasas de Alcohol/metabolismo , FN-kappa B/metabolismoRESUMEN
Squamous cell carcinoma (SCC) is one of the most common skin cancers. To develop targeted therapies for SCC, a comprehensive understanding of the disease through a systems approach is required. Here, we have collated and analyzed the literature on SCC and pathways that maintain skin homeostasis. Since, the loss of the Notch and the overactivation of the Wnt pathways in the epidermis cause SCC, we focused on these two pathways. We found that the two pathways are critical in maintaining epidermal homeostasis. Further, we found that the cancer stem cell (CSC) marker CD44 causes the transcription of SOX2, another CSC marker of SCC, activates the Wnt pathway, and blocks the Notch pathway. Similarly, the Wnt pathway causes the transcription of CD44 and SOX2 and blocks the Notch pathway. In this paper, we have discussed how the notch and the Wnt pathways affect epidermal homeostasis and the three CSCs (CD44, SOX2, and LGR6) affect the two pathways, linking the CSCs with epidermal homeostasis.
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Carcinoma de Células Escamosas , Humanos , Carcinoma de Células Escamosas/metabolismo , Epidermis/metabolismo , Vía de Señalización Wnt/genética , Homeostasis/genéticaRESUMEN
Hedgehog signaling (Hh) plays a critical role in embryogenesis. On the other hand, its overactivity may cause basal cell carcinoma (BCC), the most common human cancer. Further, epidermal and hair follicle homeostases may have a key role in the development of BCC. This article describes the importance of different signaling pathways in the different stages of the two processes. The description of the homeostases brought up the importance of the Notch signaling along with the sonic hedgehog (Shh) and the Wnt pathways. Loss of the Notch signaling adversely affects the late stages of hair follicle formation and allows the bulge cells in the hair follicles to take the fate of the keratinocytes in the interfollicular epidermis. Further, the loss of Notch activity upregulates the Shh and Wnt activities, adversely affecting the homeostases. Notably, the Notch signaling is suppressed in BCC, and the peripheral BCC cells, which have low Notch activity, show drug resistance in comparison to the interior suprabasal BCC cells, which have high Notch activity.
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Carcinoma Basocelular , Homeostasis , Neoplasias Cutáneas , Carcinoma Basocelular/genética , Carcinoma Basocelular/metabolismo , Epidermis/metabolismo , Folículo Piloso/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismoRESUMEN
Extracellular acidification occurs in inflamed tissue and the tumor microenvironment; however, a systematic study on how pH sensing contributes to tissue homeostasis is lacking. In the present study, we examine cell type-specific roles of the pH sensor G protein-coupled receptor 65 (GPR65) and its inflammatory disease-associated Ile231Leu-coding variant in inflammation control. GPR65 Ile231Leu knock-in mice are highly susceptible to both bacterial infection-induced and T cell-driven colitis. Mechanistically, GPR65 Ile231Leu elicits a cytokine imbalance through impaired helper type 17 T cell (TH17 cell) and TH22 cell differentiation and interleukin (IL)-22 production in association with altered cellular metabolism controlled through the cAMP-CREB-DGAT1 axis. In dendritic cells, GPR65 Ile231Leu elevates IL-12 and IL-23 release at acidic pH and alters endo-lysosomal fusion and degradation capacity, resulting in enhanced antigen presentation. The present study highlights GPR65 Ile231Leu as a multistep risk factor in intestinal inflammation and illuminates a mechanism by which pH sensing controls inflammatory circuits and tissue homeostasis.
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Colitis , Receptores Acoplados a Proteínas G , Animales , Colitis/metabolismo , Concentración de Iones de Hidrógeno , Inflamación/metabolismo , Lisosomas/metabolismo , Ratones , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Células Th17/metabolismoRESUMEN
Chronic inflammation is often associated with the development of tissue fibrosis, but how mesenchymal cell responses dictate pathological fibrosis versus resolution and healing remains unclear. Defining stromal heterogeneity and identifying molecular circuits driving extracellular matrix deposition and remodeling stands to illuminate the relationship between inflammation, fibrosis, and healing. We performed single-cell RNA-sequencing of colon-derived stromal cells and identified distinct classes of fibroblasts with gene signatures that are differentially regulated by chronic inflammation, including IL-11-producing inflammatory fibroblasts. We further identify a transcriptional program associated with trans-differentiation of mucosa-associated fibroblasts and define a functional gene signature associated with matrix deposition and remodeling in the inflamed colon. Our analysis supports a critical role for the metalloprotease Adamdec1 at the interface between tissue remodeling and healing during colitis, demonstrating its requirement for colon epithelial integrity. These findings provide mechanistic insight into how inflammation perturbs stromal cell behaviors to drive fibroblastic responses controlling mucosal matrix remodeling and healing.
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Proteínas ADAM/inmunología , Colitis/inmunología , Matriz Extracelular/metabolismo , Fibroblastos/inmunología , Mucosa Intestinal/inmunología , Células Madre Mesenquimatosas/inmunología , Proteínas ADAM/deficiencia , Proteínas ADAM/genética , Animales , Diferenciación Celular , Colitis/inducido químicamente , Colitis/genética , Colitis/patología , Colon/inmunología , Colon/patología , Matriz Extracelular/inmunología , Fibroblastos/patología , Fibrosis , Regulación de la Expresión Génica , Humanos , Inflamación , Interleucina-11/genética , Interleucina-11/inmunología , Mucosa Intestinal/patología , Masculino , Células Madre Mesenquimatosas/patología , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Dodecil Sulfato de Sodio/administración & dosificación , Transcripción Genética , Transcriptoma , Cicatrización de Heridas/genética , Cicatrización de Heridas/inmunologíaRESUMEN
The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator galectin-3 downstream of the Hsp90 client HIF-1α. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1α-high and/or Gal3-high cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for Hsp90/Cdc37 interface inhibitors. We therefore computationally screened >7 M compounds, and identified four novel small molecules with activities of 4 µM-44 µM in vitro. All of the compounds were K-Ras selective, and potently decreased the Hsp90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved Hsp90/Cdc37 interface inhibitors in cancer and other aging-associated diseases.
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Molecular and functional profiling of cancer cell lines is subject to laboratory-specific experimental practices and data analysis protocols. The current challenge therefore is how to make an integrated use of the omics profiles of cancer cell lines for reliable biological discoveries. Here, we carried out a systematic analysis of nine types of data modalities using meta-analysis of 53 omics studies across 12 research laboratories for 2,018 cell lines. To account for a relatively low consistency observed for certain data modalities, we developed a robust data integration approach that identifies reproducible signals shared among multiple data modalities and studies. We demonstrated the power of the integrative analyses by identifying a novel driver gene, ECHDC1, with tumor suppressive role validated both in breast cancer cells and patient tumors. The multi-modal meta-analysis approach also identified synthetic lethal partners of cancer drivers, including a co-dependency of PTEN deficient endometrial cancer cells on RNA helicases.
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Genes Supresores de Tumor , Genómica , Algoritmos , Neoplasias de la Mama/genética , Línea Celular Tumoral , Bases de Datos Genéticas , Epistasis Genética , Femenino , Humanos , Espectrometría de Masas , Reproducibilidad de los Resultados , Mutaciones Letales SintéticasRESUMEN
Tissue homeostasis is perturbed in a diversity of inflammatory pathologies. These changes can elicit endoplasmic reticulum (ER) stress, protein misfolding, and cell death. ER stress triggers the unfolded protein response (UPR), which can promote recovery of ER proteostasis and cell survival or trigger programmed cell death. Here, we leveraged single-cell RNA sequencing to define dynamic transcriptional states associated with the adaptive versus terminal UPR in the mouse intestinal epithelium. We integrated these transcriptional programs with genome-scale CRISPR screening to dissect the UPR pathway functionally. We identified QRICH1 as a key effector of the PERK-eIF2α axis of the UPR. QRICH1 controlled a transcriptional program associated with translation and secretory networks that were specifically up-regulated in inflammatory pathologies. Thus, QRICH1 dictates cell fate in response to pathological ER stress.
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Proteínas de Unión al ADN/metabolismo , Estrés del Retículo Endoplásmico/genética , Regulación de la Expresión Génica , Inflamación/metabolismo , Proteostasis/genética , Factores de Transcripción/metabolismo , Respuesta de Proteína Desplegada/genética , Animales , Apoptosis , Células Cultivadas , Proteínas de Unión al ADN/genética , Factor 2 Eucariótico de Iniciación/metabolismo , Humanos , Inflamación/genética , Inflamación/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ratones , Organoides , RNA-Seq , Análisis de la Célula Individual , Factores de Transcripción/genética , Transcripción Genética , eIF-2 Quinasa/metabolismoRESUMEN
The COVID-19 pandemic has gripped the world since January 2020 and has changed our lives in unprecedented ways. It has changed the way we work in the Operation Theatres and Intensive Care Units mainly because of the high risk of disease transmission to the healthcare workers. In order to reduce the risk of disease transmission, an understanding of the means of transmission of the virus is essential to develop a rational strategy that allows patients to receive treatment without placing either the patient or healthcare workers at risk. It should be cautioned that this is a rapidly changing field and there is a paucity of randomised controlled trials related to various aspects of the disease. It is therefore advisable to revise any recommendations in this article, as and when new evidence emerges.
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For maximal oncogenic activity, cellular MYC protein levels need to be tightly controlled so that they do not induce apoptosis. Here, we show how ubiquitin ligase UBR5 functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 ubiquitinates MYC and its effects on MYC protein stability are independent of FBXW7. Silencing of endogenous UBR5 induced MYC protein expression and regulated MYC target genes. Consistent with the tumor suppressor function of UBR5 (HYD) in Drosophila, HYD suppressed dMYC-dependent overgrowth of wing imaginal discs. In contrast, in cancer cells, UBR5 suppressed MYC-dependent priming to therapy-induced apoptosis. Of direct cancer relevance, MYC and UBR5 genes were coamplified in MYC-driven human cancers. Functionally, UBR5 suppressed MYC-mediated apoptosis in p53-mutant breast cancer cells with UBR5/MYC coamplification. Furthermore, single-cell immunofluorescence analysis demonstrated reciprocal expression of UBR5 and MYC in human basal-type breast cancer tissues. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC activity. In MYC-amplified, and p53-mutant breast cancer cells, UBR5 has an important role in suppressing MYC-mediated apoptosis priming and in protection from drug-induced apoptosis. SIGNIFICANCE: These findings identify UBR5 as a novel MYC regulator, the inactivation of which could be very important for understanding of MYC dysregulation on cancer cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1414/F1.large.jpg.
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Neoplasias de la Mama/genética , Proteínas de Unión al ADN/genética , Proteínas de Drosophila/genética , Proteínas Proto-Oncogénicas c-myc/genética , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genética , Animales , Animales Modificados Genéticamente , Apoptosis/genética , Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Femenino , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Modelos Animales , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-myc/metabolismo , RNA-Seq , Análisis de Matrices Tisulares , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación/genéticaRESUMEN
Cancer cells with heterogeneous mutation landscapes and extensive functional redundancy easily develop resistance to monotherapies by emerging activation of compensating or bypassing pathways. To achieve more effective and sustained clinical responses, synergistic interactions of multiple druggable targets that inhibit redundant cancer survival pathways are often required. Here, we report a systematic polypharmacology strategy to predict, test, and understand the selective drug combinations for MDA-MB-231 triple-negative breast cancer cells. We started by applying our network pharmacology model to predict synergistic drug combinations. Next, by utilizing kinome-wide drug-target profiles and gene expression data, we pinpointed a synergistic target interaction between Aurora B and ZAK kinase inhibition that led to enhanced growth inhibition and cytotoxicity, as validated by combinatorial siRNA, CRISPR/Cas9, and drug combination experiments. The mechanism of such a context-specific target interaction was elucidated using a dynamic simulation of MDA-MB-231 signaling network, suggesting a cross-talk between p53 and p38 pathways. Our results demonstrate the potential of polypharmacological modeling to systematically interrogate target interactions that may lead to clinically actionable and personalized treatment options.
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Aurora Quinasa B/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Aurora Quinasa B/fisiología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Interacciones Farmacológicas/genética , Sinergismo Farmacológico , Femenino , Humanos , Quinasas Quinasa Quinasa PAM/fisiología , Modelos Biológicos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
The lack of functional understanding of most mutations in cancer, combined with the non-druggability of most proteins, challenge genomics-based identification of oncology drug targets. We implemented a machine-learning-based approach (idTRAX), which relates cell-based screening of small-molecule compounds to their kinase inhibition data, to directly identify effective and readily druggable targets. We applied idTRAX to triple-negative breast cancer cell lines and efficiently identified cancer-selective targets. For example, we found that inhibiting AKT selectively kills MFM-223 and CAL148 cells, while inhibiting FGFR2 only kills MFM-223. Since the effects of catalytically inhibiting a protein can diverge from those of reducing its levels, targets identified by idTRAX frequently differ from those identified through gene knockout/knockdown methods. This is critical if the purpose is to identify targets specifically for small-molecule drug development, whereby idTRAX may produce fewer false-positives. The rapid nature of the approach suggests that it may be applicable in personalizing therapy.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Ensayos de Selección de Medicamentos Antitumorales/métodos , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Detección Precoz del Cáncer/métodos , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Aprendizaje Automático , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
High-throughput drug sensitivity testing provides a powerful phenotypic profiling approach to identify effective drug candidates for individual cell lines or patient-derived samples. Here, we describe an experimental-computational pipeline, named target addiction scoring (TAS), which mathematically transforms the drug response profiles into target addiction signatures, and thereby provides a ranking of potential therapeutic targets according to their functional importance in a particular cancer sample. The TAS pipeline makes use of drug polypharmacology to integrate the drug sensitivity and selectivity profiles through systems-wide interconnection networks between drugs and their targets, including both primary protein targets as well as secondary off-targets. We show how the TAS pipeline enables one to identify not only single-target addictions but also combinatorial coaddictions among targets that often underlie synergistic drug combinations.
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Antineoplásicos/farmacología , Biología Computacional/métodos , Resistencia a Antineoplásicos/efectos de los fármacos , Polifarmacología , Combinación de Medicamentos , Sinergismo Farmacológico , Humanos , Programas InformáticosRESUMEN
Drug Target Commons (DTC) is a web platform (database with user interface) for community-driven bioactivity data integration and standardization for comprehensive mapping, reuse and analysis of compound-target interaction profiles. End users can search, upload, edit, annotate and export expert-curated bioactivity data for further analysis, using an application programmable interface, database dump or tab-delimited text download options. To guide chemical biology and drug-repurposing applications, DTC version 2.0 includes updated clinical development information for the compounds and target gene-disease associations, as well as cancer-type indications for mutant protein targets, which are critical for precision oncology developments.
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Interacciones Farmacológicas , Programas Informáticos , Algoritmos , Bioensayo , Minería de Datos , Bases de Datos de Proteínas , Internet , Mutación/genética , Interfaz Usuario-ComputadorRESUMEN
Knowledge of the full target space of bioactive substances, approved and investigational drugs as well as chemical probes, provides important insights into therapeutic potential and possible adverse effects. The existing compound-target bioactivity data resources are often incomparable due to non-standardized and heterogeneous assay types and variability in endpoint measurements. To extract higher value from the existing and future compound target-profiling data, we implemented an open-data web platform, named Drug Target Commons (DTC), which features tools for crowd-sourced compound-target bioactivity data annotation, standardization, curation, and intra-resource integration. We demonstrate the unique value of DTC with several examples related to both drug discovery and drug repurposing applications and invite researchers to join this community effort to increase the reuse and extension of compound bioactivity data.