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Abril-Fornaguera JAutor o CoautorVillanueva AAutor o CoautorLlovet JmAutor o Coautor

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7 de agosto de 2023
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Artículo

WNTinib is a multi-kinase inhibitor with specificity against β-catenin mutant hepatocellular carcinoma

Publicado en: Nature Cancer. 4 (8): 1157-+ - 2023-08-03 4(8), DOI: 10.1038/s43018-023-00609-9

Autores:

Rialdi, A; Duffy, M; Scopton, AP; Fonseca, F; Zhao, JN; Schwarz, M; Molina-Sanchez, P; Mzoughi, S; Arceci, E; Abril-Fornaguera, J; Meadows, A; de Galarreta, MR; Torre, D; Reyes, K; Lim, YT; Rosemann, F; Khan, ZM; Mohammed, K; Wang, XD; Yu, XF; Lakshmanan, M; Rajarethinam, R; Tan, SY; Jin, J; Villanueva, A; Michailidis, E; De Jong, YP; Rice, CM; Marazzi, I; Hasson, D; Llovet, JM; Sobota, RM; Lujambio, A; Guccione, E; Dar, AC
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Afiliaciones

Bioinformatics for Next Generation Sequencing Shared Resource Facility, Icahn School of Medicine at Mount Sinai, New York, NY, USA. - Autor o Coautor
Bioinformatics for Next Generation Sequencing Shared Resource Facility, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernesto.guccione@mssm.edu. - Autor o Coautor
Center for OncoGenomics and Innovative Therapeutics, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. - Autor o Coautor
Center for OncoGenomics and Innovative Therapeutics, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernesto.guccione@mssm.edu. - Autor o Coautor
Center for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. - Autor o Coautor
Center for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. dara1@mskcc.org. - Autor o Coautor
Center for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernesto.guccione@mssm.edu. - Autor o Coautor
Department of Biological Cancer, University of California Irvine, Orange, CA, USA. - Autor o Coautor
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, USA. - Autor o Coautor
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. - Autor o Coautor
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. amaia.lujambio@mssm.edu. - Autor o Coautor
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. dara1@mskcc.org. - Autor o Coautor
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernesto.guccione@mssm.edu. - Autor o Coautor
Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA. - Autor o Coautor
Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. - Autor o Coautor
Emory Univ, Sch Med, Dept Pediat, Lab Biochem Pharmacol, Atlanta, GA USA - Autor o Coautor
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. - Autor o Coautor
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. amaia.lujambio@mssm.edu. - Autor o Coautor
Icahn Sch Med Mt Sinai, Bioinformat Next Generat Sequencing Shared Resourc, New York, NY 10029 USA - Autor o Coautor
Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA - Autor o Coautor
Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA - Autor o Coautor
Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, New York, NY 10029 USA - Autor o Coautor
Icahn Sch Med Mt Sinai, Precis Immunol Inst, New York, NY 10029 USA - Autor o Coautor
Icahn Sch Med Mt Sinai, Tisch Canc Inst, Ctr OncoGen & Innovat Therapeut, New York, NY 10029 USA - Autor o Coautor
Icahn Sch Med Mt Sinai, Tisch Canc Inst, Ctr Therapeut Discovery, Dept Oncol Sci & Pharmacol Sci, New York, NY 10029 USA - Autor o Coautor
Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Med, Liver Canc Program, New York, NY 10029 USA - Autor o Coautor
Icahn Sch Med Mt Sinai, Tsch Canc Inst, Div Hematol & Med Oncol, New York, NY 10029 USA - Autor o Coautor
Inst Mol & Cell Biol, Agcy Sci Technol & Res, Singapore, Singapore - Autor o Coautor
Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain. - Autor o Coautor
Institucio Catalana Recerca Estudis Avancats, Barcelona, Spain - Autor o Coautor
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore. - Autor o Coautor
Laboratory of Biochemical Pharmacology, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA. - Autor o Coautor
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. - Autor o Coautor
Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. - Autor o Coautor
Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. amaia.lujambio@mssm.edu. - Autor o Coautor
Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernesto.guccione@mssm.edu. - Autor o Coautor
Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA - Autor o Coautor
Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore, Singapore - Autor o Coautor
Program in Chemical Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. dara1@mskcc.org. - Autor o Coautor
Rockefeller Univ, Lab Virol & Infect Dis, New York, NY USA - Autor o Coautor
The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. - Autor o Coautor
The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. amaia.lujambio@mssm.edu. - Autor o Coautor
The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernesto.guccione@mssm.edu. - Autor o Coautor
Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain. - Autor o Coautor
Univ Barcelona, Hosp Clin, Liver Unit, Translat Res Hepat Oncol,IDIBAPS, Barcelona, Spain - Autor o Coautor
Univ Calif Irvine, Dept Biol Canc, Orange, CA USA - Autor o Coautor
Weill Cornell Med, Div Gastroenterol & Hepatol, New York, NY USA - Autor o Coautor
Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. - Autor o Coautor
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Resumen

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. β-Catenin (CTNNB1)-mutated HCC represents 30% of cases of the disease with no precision therapeutics available. Using chemical libraries derived from clinical multi-kinase inhibitor (KI) scaffolds, we screened HCC organoids to identify WNTinib, a KI with exquisite selectivity in CTNNB1-mutated human and murine models, including patient samples. Multiomic and target engagement analyses, combined with rescue experiments and in vitro and in vivo efficacy studies, revealed that WNTinib is superior to clinical KIs and inhibits KIT/mitogen-activated protein kinase (MAPK) signaling at multiple nodes. Moreover, we demonstrate that reduced engagement on BRAF and p38α kinases by WNTinib relative to several multi-KIs is necessary to avoid compensatory feedback signaling-providing a durable and selective transcriptional repression of mutant β-catenin/Wnt targets through nuclear translocation of the EZH2 transcriptional repressor. Our studies uncover a previously unknown mechanism to harness the KIT/MAPK/EZH2 pathway to potently and selectively antagonize CTNNB1-mutant HCC with an unprecedented wide therapeutic index.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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Palabras clave

3 [3 bromo 4 (2,4 difluorobenzyloxy) 6 methyl 2 oxo 1(2h) pyridinyl] n,4 dimethylbenzamide4 (4 fluorophenyl) 2 (4 hydroxyphenyl) 5 (4 pyridyl)imidazoleAnimalAnimal experimentAnimal modelAnimalsAntineoplastic agentAntineoplastic agentsArticleAxitinibB raf kinaseBeta cateninBlood samplingBody weight changeCanonical wnt signalingCarcinoma, hepatocellularCaspase 3Caspase 7Cell fractionationCell viabilityControlled studyDose responseDown regulationDrug antagonismDrug mechanismDrug specificityDrug toxicityFemaleGene mutationGenetic transfectionGeneticsGenotypingHek293t cell lineHep 3b2.1-7 cell lineHep-g2 cell lineHumanHuman cellHumansImmunofluorescence assayLiver cell carcinomaLiver neoplasmsLiver tumorLuciferase assayMass spectrometryMedian survival timeMetabolismMiceMitogen activated protein kinase p38Molecular cloningMolecular dockingMouseMultiomicsNonhumanOrganoidPhosphoproteomicsProtein expression levelProtein kinase inhibitorProtein kinase inhibitorsProtein localizationReal time polymerase chain reactionRegorafenibResazurin assayResistance,discovery,targets,liver,cell,raShc 772984Snu-182 cell lineSnu-398 cell lineSnu-475 cell lineSorafenibTranscription factorTranscription factor ezh2Transcription factorsTumor volumeUnclassified drugVemurafenibWestern blottingWntinib

Indicios de calidad

Impacto bibliométrico. Análisis de la aportación y canal de difusión

El trabajo ha sido publicado en la revista Nature Cancer debido a la progresión y el buen impacto que ha alcanzado en los últimos años, según la agencia WoS (JCR), se ha convertido en una referencia en su campo. En el año de publicación del trabajo, 2023, se encontraba en la posición 11/322, consiguiendo con ello situarse como revista Q1 (Primer Cuartil), en la categoría Oncology. Destacable, igualmente, el hecho de que la Revista está posicionada por encima del Percentil 90.

Desde una perspectiva relativa, y atendiendo al indicador del impacto normalizado calculado a partir de las Citas Mundiales proporcionadas por WoS (ESI, Clarivate), arroja un valor para la normalización de citas relativas a la tasa de citación esperada de: 3.08. Esto indica que, de manera comparada con trabajos en la misma disciplina y en el mismo año de publicación, lo ubica como trabajo citado por encima de la media. (fuente consultada: ESI 13 Nov 2025)

Esta información viene reforzada por otros indicadores del mismo tipo, que aunque dinámicos en el tiempo y dependientes del conjunto de citaciones medias mundiales en el momento de su cálculo, coinciden en posicionar en algún momento al trabajo, entre el 50% más citados dentro de su temática:

  • Media Ponderada del Impacto Normalizado de la agencia Scopus: 2.08 (fuente consultada: FECYT Mar 2025)

De manera concreta y atendiendo a las diferentes agencias de indexación, el trabajo ha acumulado, hasta la fecha 2026-01-01, el siguiente número de citas:

  • WoS: 17
  • Scopus: 15
  • Europe PMC: 3
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Impacto y visibilidad social

Desde la dimensión de Influencia o adopción social, y tomando como base las métricas asociadas a las menciones e interacciones proporcionadas por agencias especializadas en el cálculo de las denominadas “Métricas Alternativas o Sociales”, podemos destacar a fecha 2026-01-01:

  • El uso, desde el ámbito académico evidenciado por el indicador de la agencia Altmetric referido como agregaciones realizadas por el gestor bibliográfico personal Mendeley, nos da un total de: 36.
  • La utilización de esta aportación en marcadores, bifurcaciones de código, añadidos a listas de favoritos para una lectura recurrente, así como visualizaciones generales, indica que alguien está usando la publicación como base de su trabajo actual. Esto puede ser un indicador destacado de futuras citas más formales y académicas. Tal afirmación es avalada por el resultado del indicador “Capture” que arroja un total de: 37 (PlumX).

Con una intencionalidad más de divulgación y orientada a audiencias más generales podemos observar otras puntuaciones más globales como:

  • El Score total de Altmetric: 46.
  • El número de menciones en la red social X (antes Twitter): 66 (Altmetric).
  • El número de menciones en medios de comunicación: 1 (Altmetric).

Es fundamental presentar evidencias que respalden la plena alineación con los principios y directrices institucionales en torno a la Ciencia Abierta y la Conservación y Difusión del Patrimonio Intelectual. Un claro ejemplo de ello es:

  • El trabajo se ha enviado a una revista cuya política editorial permite la publicación en abierto Open Access.
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Análisis de liderazgo de los autores institucionales

Este trabajo se ha realizado con colaboración internacional, concretamente con investigadores de: Singapore; United States of America.

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Reconocimientos ligados al ítem

Research reported in this publication was supported in part by the National Cancer Institute (NCI) of the National Institutes of Health (NIH: grant no. R01 CA256480-01) and an ISMMS seed fund to E.G. We thank the Tisch Cancer Institute for the use of the services and facilities supported by the NCI Cancer Center Support Grant (no. P30 CA196521). E.G. and A.C.D. thank the Mark Foundation for the Cancer Research Aspire award. E.G., A.C.D. and J.L. thank Alex's Lemonade Stand Foundation for Childhood Cancer for support. M.S. was supported by an NCI training grant (no. T32CA078207). A.R. was supported by an NCI training grant, NCI F32 fellowship and K99 fellowship (grant nos. T32CA078207-16A1, F32CA247414-01 and 1K99CA273538-01). M.D. is a recipient of the T32 fellowship (grant no. 5T32GM062754). We are grateful for support from the NIH for grant nos. R01AI143295 (to C.M.R.) and R01AA027327 (to Y.P.D.J.). Further support was provided by the Robertson Therapeutic Development Fund (to E.M. and C.M.R.) and the Center for Basic and Translational Research on Disorders of the Digestive System through the generosity of the Leona M. and Harry B. Helmsley Charitable Trust (to E.M.). A.L. is supported by a Damon Runyon-Rachleff Innovation Award (no. DR52-18), Pfizer Emerging Science Fund, NIH/NCI R37 Merit Award (no. R37CA230636) and NIH/NCI (grant no. R01 CA256480-01). The Dar laboratory (M.D., A.P.S., Z.M.K. and A.C.D.) were supported by innovation awards from the NIH (no. 1DP2CA186570-01) and Damon Runyan Rachleff Foundation, as well as NIH grants (nos. R01CA227636, R01CA258736 and R01 CA256480-01). A.C.D. thanks the following for their support as a the Pew-Stewart Scholar in Cancer Research, Young Investigator of the Pershing-Square Sohn Cancer Research Alliance and Mark Foundation Aspire Awardee. J.J. acknowledges the support by grants (nos. R01CA218600, R01CA230854 and R01CA268519) from the NIH. This work utilized the NMR Spectrometer Systems at Mount Sinai acquired with funding from NIH SIG grants (nos. 1S10OD025132 and 1S10OD028504). J.M.L. is supported by grants from the NIH (nos. R01 DK128289-01), HUNTER-CRUK/AECC/FAIRC (ref. no. C9380/A26813), Samuel Waxman Cancer Research Foundation, the Spanish National Health Institute (MICINN, grant no. PID2019-105378RB-I00) and the Generalitat de Catalunya (AGAUR, grant no. SGR-1358). J.A.F. is supported by the University of Barcelona (PREDOCS-UB) and the Societat Catalana de Digestologia. This research was conducted with the support of the Biorepository and Pathology Core at ISMMS. We thank Dr. Rachel Brody and team members for this support. We thank the ISMMS Liver Cancer Program's surgeons, Drs. Myron Schwartz, Parissa Tabrizian, Ganesh Gunasekaran and Umut Sarpel. We also thank Drs. Meritxell Huch and Laura Broutier for their initial help with setting up organoid cultures.
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