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2.
Cancer Discov ; 14(4): 663-668, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38571421

RESUMEN

SUMMARY: We are building the world's first Virtual Child-a computer model of normal and cancerous human development at the level of each individual cell. The Virtual Child will "develop cancer" that we will subject to unlimited virtual clinical trials that pinpoint, predict, and prioritize potential new treatments, bringing forward the day when no child dies of cancer, giving each one the opportunity to lead a full and healthy life.


Asunto(s)
Neoplasias , Humanos , Neoplasias/genética
3.
Mol Cancer Ther ; 23(6): 791-808, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38412481

RESUMEN

Therapies that abrogate persistent androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BCL-2-associated athanogene-1 (BAG-1) mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC. In addition, interrogation of geometric and physiochemical properties of the BAG domain of BAG-1 isoforms identifies it to be a tractable but challenging drug target. Furthermore, through BAG-1 isoform mouse knockout studies, we confirm that BAG-1 isoforms regulate hormone physiology and that therapies targeting the BAG domain will be associated with limited "on-target" toxicity. Importantly, the postulated inhibitor of BAG-1 isoforms, Thio-2, suppressed AR signaling and other important pathways implicated in the development and progression of CRPC to reduce the growth of treatment-resistant prostate cancer cell lines and patient-derived models. However, the mechanism by which Thio-2 elicits the observed phenotype needs further elucidation as the genomic abrogation of BAG-1 isoforms was unable to recapitulate the Thio-2-mediated phenotype. Overall, these data support the interrogation of related compounds with improved drug-like properties as a novel therapeutic approach in CRPC, and further highlight the clinical potential of treatments that block persistent AR signaling which are currently undergoing clinical evaluation in CRPC.


Asunto(s)
Progresión de la Enfermedad , Neoplasias de la Próstata Resistentes a la Castración , Transducción de Señal , Masculino , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Humanos , Animales , Ratones , Transducción de Señal/efectos de los fármacos , Receptores Androgénicos/metabolismo , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proliferación Celular , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos
4.
Patterns (N Y) ; 4(8): 100777, 2023 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-37602223

RESUMEN

Survival models exist to study relationships between biomarkers and treatment effects. Deep learning-powered survival models supersede the classical Cox proportional hazards (CoxPH) model, but substantial performance drops were observed on high-dimensional features because of irrelevant/redundant information. To fill this gap, we proposed SwarmDeepSurv by integrating swarm intelligence algorithms with the deep survival model. Furthermore, four objective functions were designed to optimize prognostic prediction while regularizing selected feature numbers. When testing on multicenter sets (n = 1,058) of four different cancer types, SwarmDeepSurv was less prone to overfitting and achieved optimal patient risk stratification compared with popular survival modeling algorithms. Strikingly, SwarmDeepSurv selected different features compared with classical feature selection algorithms, including the least absolute shrinkage and selection operator (LASSO), with nearly no feature overlapping across these models. Taken together, SwarmDeepSurv offers an alternative approach to model relationships between radiomics features and survival endpoints, which can further extend to study other input data types including genomics.

5.
Nucleic Acids Res ; 51(D1): D1212-D1219, 2023 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-36624665

RESUMEN

canSAR (https://cansar.ai) is the largest public cancer drug discovery and translational research knowledgebase. Now hosted in its new home at MD Anderson Cancer Center, canSAR integrates billions of experimental measurements from across molecular profiling, pharmacology, chemistry, structural and systems biology. Moreover, canSAR applies a unique suite of machine learning algorithms designed to inform drug discovery. Here, we describe the latest updates to the knowledgebase, including a focus on significant novel data. These include canSAR's ligandability assessment of AlphaFold; mapping of fragment-based screening data; and new chemical bioactivity data for novel targets. We also describe enhancements to the data and interface.


Asunto(s)
Antineoplásicos , Descubrimiento de Drogas , Bases del Conocimiento , Investigación Biomédica Traslacional , Humanos , Algoritmos , Neoplasias/tratamiento farmacológico , Neoplasias/genética
6.
Nucleic Acids Res ; 51(D1): D1492-D1502, 2023 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-36268860

RESUMEN

We describe the Chemical Probes Portal (https://www.chemicalprobes.org/), an expert review-based public resource to empower chemical probe assessment, selection and use. Chemical probes are high-quality small-molecule reagents, often inhibitors, that are important for exploring protein function and biological mechanisms, and for validating targets for drug discovery. The publication, dissemination and use of chemical probes provide an important means to accelerate the functional annotation of proteins, the study of proteins in cell biology, physiology, and disease pathology, and to inform and enable subsequent pioneering drug discovery and development efforts. However, the widespread use of small-molecule compounds that are claimed as chemical probes but are lacking sufficient quality, especially being inadequately selective for the desired target or even broadly promiscuous in behaviour, has resulted in many erroneous conclusions in the biomedical literature. The Chemical Probes Portal was established as a public resource to aid the selection and best-practice use of chemical probes in basic and translational biomedical research. We describe the background, principles and content of the Portal and its technical development, as well as examples of its applications and use. The Chemical Probes Portal is a community resource and we therefore describe how researchers can be involved in its content and development.


Asunto(s)
Sondas Moleculares , Proteínas , Descubrimiento de Drogas , Proteínas/química , Proteínas/metabolismo , Bases de Datos de Compuestos Químicos
7.
J Cheminform ; 14(1): 28, 2022 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-35643512

RESUMEN

BACKGROUND: Integration of medicinal chemistry data from numerous public resources is an increasingly important part of academic drug discovery and translational research because it can bring a wealth of important knowledge related to compounds in one place. However, different data sources can report the same or related compounds in various forms (e.g., tautomers, racemates, etc.), thus highlighting the need of organising related compounds in hierarchies that alert the user on important bioactivity data that may be relevant. To generate these compound hierarchies, we have developed and implemented canSARchem, a new compound registration and standardization pipeline as part of the canSAR public knowledgebase. canSARchem builds on previously developed ChEMBL and PubChem pipelines and is developed using KNIME. We describe the pipeline which we make publicly available, and we provide examples on the strengths and limitations of the use of hierarchies for bioactivity data exploration. Finally, we identify canonicalization enrichment in FDA-approved drugs, illustrating the benefits of our approach. RESULTS: We created a chemical registration and standardization pipeline in KNIME and made it freely available to the research community. The pipeline consists of five steps to register the compounds and create the compounds' hierarchy: 1. Structure checker, 2. Standardization, 3. Generation of canonical tautomers and representative structures, 4. Salt strip, and 5. Generation of abstract structure to generate the compound hierarchy. Unlike ChEMBL's RDKit pipeline, we carry out compound canonicalization ahead of getting the parent structure, similar to PubChem's OpenEye pipeline. canSARchem has a lower rejection rate compared to both PubChem and ChEMBL. We use our pipeline to assess the impact of grouping the compounds in hierarchies for bioactivity data exploration. We find that FDA-approved drugs show statistically significant sensitivity to canonicalization compared to the majority of bioactive compounds which demonstrates the importance of this step. CONCLUSIONS: We use canSARchem to standardize all the compounds uploaded in canSAR (> 3 million) enabling efficient data integration and the rapid identification of alternative compound forms with useful bioactivity data. Comparison with PubChem and ChEMBL pipelines evidenced comparable performances in compound standardization, but only PubChem and canSAR canonicalize tautomers and canSAR has a slightly lower rejection rate. Our results highlight the importance of compound hierarchies for bioactivity data exploration. We make canSARchem available under a Creative Commons Attribution-ShareAlike 4.0 International License (CC BY-SA 4.0) at https://gitlab.icr.ac.uk/cansar-public/compound-registration-pipeline .

8.
Mol Cancer Ther ; 21(6): 1020-1029, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35368084

RESUMEN

We hypothesize that the study of acute protein perturbation in signal transduction by targeted anticancer drugs can predict drug sensitivity of these agents used as single agents and rational combination therapy. We assayed dynamic changes in 52 phosphoproteins caused by an acute exposure (1 hour) to clinically relevant concentrations of seven targeted anticancer drugs in 35 non-small cell lung cancer (NSCLC) cell lines and 16 samples of NSCLC cells isolated from pleural effusions. We studied drug sensitivities across 35 cell lines and synergy of combinations of all drugs in six cell lines (252 combinations). We developed orthogonal machine-learning approaches to predict drug response and rational combination therapy. Our methods predicted the most and least sensitive quartiles of drug sensitivity with an AUC of 0.79 and 0.78, respectively, whereas predictions based on mutations in three genes commonly known to predict response to the drug studied, for example, EGFR, PIK3CA, and KRAS, did not predict sensitivity (AUC of 0.5 across all quartiles). The machine-learning predictions of combinations that were compared with experimentally generated data showed a bias to the highest quartile of Bliss synergy scores (P = 0.0243). We confirmed feasibility of running such assays on 16 patient samples of freshly isolated NSCLC cells from pleural effusions. We have provided proof of concept for novel methods of using acute ex vivo exposure of cancer cells to targeted anticancer drugs to predict response as single agents or combinations. These approaches could complement current approaches using gene mutations/amplifications/rearrangements as biomarkers and demonstrate the utility of proteomics data to inform treatment selection in the clinic.


Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Derrame Pleural , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inteligencia Artificial , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutación
9.
RSC Med Chem ; 13(1): 13-21, 2022 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-35211674

RESUMEN

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.

10.
Cell Chem Biol ; 28(10): 1433-1445.e3, 2021 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-34077750

RESUMEN

Most small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we use computational and experimental methods to identify and systematically characterize the kinase cross-pharmacology of representative HSP90 inhibitors. We demonstrate that the resorcinol clinical candidates ganetespib and, to a lesser extent, luminespib, display unique off-target kinase pharmacology as compared with other HSP90 inhibitors. We also demonstrate that polypharmacology evolved during the optimization to discover luminespib and that the hit, leads, and clinical candidate all have different polypharmacological profiles. We therefore recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities.


Asunto(s)
Descubrimiento de Drogas , Evolución Molecular , Proteínas HSP90 de Choque Térmico/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Sitios de Unión , Receptor con Dominio Discoidina 1/antagonistas & inhibidores , Receptor con Dominio Discoidina 1/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Isoxazoles/química , Isoxazoles/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-abl/metabolismo , Resorcinoles/química , Resorcinoles/metabolismo , Triazoles/química , Triazoles/metabolismo
11.
Cancer Res ; 81(4): 1087-1100, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33822745

RESUMEN

Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P < 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease. SIGNIFICANCE: This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.


Asunto(s)
Histona Demetilasas con Dominio de Jumonji/fisiología , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/genética , Empalme Alternativo , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Estudios de Cohortes , Inhibidores Enzimáticos/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Humanos , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Histona Demetilasas con Dominio de Jumonji/genética , Masculino , Terapia Molecular Dirigida , Oxigenasas/genética , Oxigenasas/fisiología , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Androgénicos/química , Receptores Androgénicos/metabolismo , Estudios Retrospectivos
12.
Nucleic Acids Res ; 49(D1): D1074-D1082, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33219674

RESUMEN

canSAR (http://cansar.icr.ac.uk) is the largest, public, freely available, integrative translational research and drug discovery knowledgebase for oncology. canSAR integrates vast multidisciplinary data from across genomic, protein, pharmacological, drug and chemical data with structural biology, protein networks and more. It also provides unique data, curation and annotation and crucially, AI-informed target assessment for drug discovery. canSAR is widely used internationally by academia and industry. Here we describe significant developments and enhancements to the data, web interface and infrastructure of canSAR in the form of the new implementation of the system: canSARblack. We demonstrate new functionality in aiding translation hypothesis generation and experimental design, and show how canSAR can be adapted and utilised outside oncology.


Asunto(s)
Biología Computacional/métodos , Bases de Datos Genéticas , Descubrimiento de Drogas/métodos , Bases del Conocimiento , Neoplasias/genética , Investigación Biomédica Traslacional/métodos , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Minería de Datos/métodos , Genómica/métodos , Humanos , Internet , Oncología Médica/métodos , Estructura Molecular , Neoplasias/metabolismo , Proteómica/métodos , Interfaz Usuario-Computador
13.
J Phys Chem Lett ; 12(1): 49-58, 2021 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-33300337

RESUMEN

Water plays a key role in biomolecular recognition and binding. Despite the development of several computational and experimental approaches, it is still challenging to comprehensively characterize water-mediated effects on the binding process. Here, we investigate how water affects the binding of Src kinase to one of its inhibitors, PP1. Src kinase is a target for treating several diseases, including cancer. We use biased molecular dynamics simulations, where the hydration of predetermined regions is tuned at will. This computational technique efficiently accelerates the SRC-PP1 binding simulation and allows us to identify several key and yet unexplored aspects of the solvent's role. This study provides a further perspective on the binding phenomenon, which may advance the current drug design approaches for the development of new kinase inhibitors.


Asunto(s)
Inhibidores de Proteínas Quinasas/metabolismo , Familia-src Quinasas/metabolismo , Ligandos , Simulación de Dinámica Molecular , Unión Proteica , Conformación Proteica , Inhibidores de Proteínas Quinasas/farmacología , Termodinámica , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/química
14.
Future Med Chem ; 13(8): 731-747, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-31778323

RESUMEN

High-quality small molecule chemical probes are extremely valuable for biological research and target validation. However, frequent use of flawed small-molecule inhibitors produces misleading results and diminishes the robustness of biomedical research. Several public resources are available to facilitate assessment and selection of better chemical probes for specific protein targets. Here, we review chemical probe resources, discuss their current strengths and limitations, and make recommendations for further improvements. Expert review resources provide in-depth analysis but currently cover only a limited portion of the liganded proteome. Computational resources encompass more proteins and are regularly updated, but have limitations in data availability and curation. We show how biomedical scientists may use these resources to choose the best available chemical probes for their research.


Asunto(s)
Inhibidores Enzimáticos/química , Sondas Moleculares/química , Proteínas/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Algoritmos , Animales , Simulación por Computador , Bases de Datos de Compuestos Químicos , Inhibidores Enzimáticos/farmacología , Humanos , Sondas Moleculares/farmacología , Proteoma/química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad
15.
Sci Rep ; 10(1): 16000, 2020 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-32994435

RESUMEN

Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an important role in tumour biology by promoting the stabilisation and activity of oncogenic 'client' proteins. Inhibition of Hsp90 by small-molecule drugs, acting via its ATP hydrolysis site, has shown promise as a molecularly targeted cancer therapy. Owing to the importance of Hop and other tetratricopeptide repeat (TPR)-containing cochaperones in regulating Hsp90 activity, the Hsp90-TPR domain interface is an alternative site for inhibitors, which could result in effects distinct from ATP site binders. The TPR binding site of Hsp90 cochaperones includes a shallow, positively charged groove that poses a significant challenge for druggability. Herein, we report the apo, solution-state structure of Hop TPR2A which enables this target for NMR-based screening approaches. We have designed prototype TPR ligands that mimic key native 'carboxylate clamp' interactions between Hsp90 and its TPR cochaperones and show that they block binding between Hop TPR2A and the Hsp90 C-terminal MEEVD peptide. We confirm direct TPR-binding of these ligands by mapping 1H-15N HSQC chemical shift perturbations to our new NMR structure. Our work provides a novel structure, a thorough assessment of druggability and robust screening approaches that may offer a potential route, albeit difficult, to address the chemically challenging nature of the Hop TPR2A target, with relevance to other TPR domain interactors.


Asunto(s)
Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Dominio Catalítico , Simulación por Computador , Humanos , Ligandos , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Unión Proteica , Conformación Proteica , Dominios Proteicos , Bibliotecas de Moléculas Pequeñas/química
17.
Sci Rep ; 10(1): 2585, 2020 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-32066817

RESUMEN

Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles.


Asunto(s)
Antineoplásicos/química , Indazoles/química , Indoles/química , Ftalazinas/química , Piperazinas/química , Piperidinas/química , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Sitios de Unión , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Células HEK293 , Humanos , Indazoles/administración & dosificación , Indazoles/efectos adversos , Indoles/administración & dosificación , Indoles/efectos adversos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/patología , Ftalazinas/administración & dosificación , Ftalazinas/efectos adversos , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Polifarmacología , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Secundaria de Proteína , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Especificidad por Sustrato , Quinasas DyrK
18.
Eur J Cancer ; 121: 224-235, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31543384

RESUMEN

BACKGROUND: For children with cancer, the clinical integration of precision medicine to enable predictive biomarker-based therapeutic stratification is urgently needed. METHODS: We have developed a hybrid-capture next-generation sequencing (NGS) panel, specifically designed to detect genetic alterations in paediatric solid tumours, which gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. In this study, we offered an NGS panel, with clinical reporting via a molecular tumour board for children with solid tumours. Furthermore, for a cohort of 12 patients, we used a circulating tumour DNA (ctDNA)-specific panel to sequence ctDNA from matched plasma samples and compared plasma and tumour findings. RESULTS: A total of 255 samples were submitted from 223 patients for the NGS panel. Using FFPE tissue, 82% of all submitted samples passed quality control for clinical reporting. At least one genetic alteration was detected in 70% of sequenced samples. The overall detection rate of clinically actionable alterations, defined by modified OncoKB criteria, for all sequenced samples was 51%. A total of 8 patients were sequenced at different stages of treatment. In 6 of these, there were differences in the genetic alterations detected between time points. Sequencing of matched ctDNA in a cohort of extracranial paediatric solid tumours also identified a high detection rate of somatic alterations in plasma. CONCLUSION: We demonstrate that tailored clinical molecular profiling of both tumour DNA and plasma-derived ctDNA is feasible for children with solid tumours. Furthermore, we show that a targeted NGS panel-based approach can identify actionable genetic alterations in a high proportion of patients.


Asunto(s)
ADN Tumoral Circulante/genética , ADN de Neoplasias/genética , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Medicina de Precisión/métodos , Transcriptoma , Adolescente , Biomarcadores de Tumor/genética , Biopsia , Niño , Preescolar , ADN Tumoral Circulante/análisis , ADN de Neoplasias/análisis , Estudios de Factibilidad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Lactante , Masculino , Análisis por Apareamiento , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Neoplasias/sangre , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patología , Proyectos Piloto , Valor Predictivo de las Pruebas , Adulto Joven
19.
Oncogene ; 38(30): 5905-5920, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31296956

RESUMEN

Deregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) is highly prevalent in cancer; yet, inhibitors against these kinases are currently used only in restricted tumour contexts. The extent to which cancers depend on CDK4/6 and the mechanisms that may undermine such dependency are poorly understood. Here, we report that signalling engaging the MET proto-oncogene receptor tyrosine kinase/focal adhesion kinase (FAK) axis leads to CDK4/6-independent CDK2 activation, involving as critical mechanistic events loss of the CDKI p21CIP1 and gain of its regulator, the ubiquitin ligase subunit SKP2. Combined inhibition of MET/FAK and CDK4/6 eliminates the proliferation capacity of cancer cells in culture, and enhances tumour growth inhibition in vivo. Activation of the MET/FAK axis is known to arise through cancer extrinsic and intrinsic cues. Our work predicts that such cues support cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases and identifies MET/FAK as a tractable route to broaden the utility of CDK4/6 inhibitor-based therapies in the clinic.


Asunto(s)
Ciclo Celular , División Celular , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Células A549 , Animales , Biomarcadores de Tumor/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Xenoinjertos , Humanos , Ratones , Proto-Oncogenes Mas
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