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Analysis of institutional authors

Abril-Fornaguera JAuthorVillanueva AAuthorLlovet JmAuthor

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August 7, 2023
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Article

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

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

Authors:

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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Affiliations

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

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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Keywords

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

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Nature Cancer due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2023, it was in position 11/322, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 3.08. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 13, 2025)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 2.08 (source consulted: FECYT Mar 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-12-31, the following number of citations:

  • WoS: 17
  • Scopus: 15
  • Europe PMC: 3
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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-12-31:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 36.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 37 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 46.
  • The number of mentions on the social network X (formerly Twitter): 66 (Altmetric).
  • The number of mentions in news outlets: 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
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Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Singapore; United States of America.

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Awards linked to the item

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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