ArticleNature cancer2023
WNTinib is a multi-kinase inhibitor with specificity against β-catenin mutant hepatocellular carcinoma.
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Article in Nature cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23citing papers in PubMed
6.1field-weighted citation impact, top 3% of its field
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Who cites it
23 citing papers in PubMed, 24 citations in OpenAlex.
- E7386 Enhances Lenvatinib's Antitumor Activity in Preclinical Models and Human Hepatocellular Carcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Positive selection screen identifies natural product β-catenin inactivators.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Wnt/β-catenin signaling in hepatocellular carcinoma: a key player in resistance to targeted and immunotherapies.Carcinogenesis · 2026Review
- Targeting the 4EBP1/HSP90β/Nrf2 Axis Sensitizes β-catenin-mutant Hepatocellular Carcinoma to mTOR Inhibitors via Ferroptosis Induction.Journal of clinical and translational hepatology · 2026Article
- An appendiceal cancer organoid biobank identifies phenotypic evolution and druggable dependencies of peritoneal carcinomatosis.Developmental cell · 2026Article
- Advancing Systemic Treatment beyond First Line for Advanced Hepatocellular Carcinoma.Current oncology reports · 2026Review
- Integrated genomic analyses identify oncogenic pathway interplay in hepatocarcinogenesis defining specific molecular subtypes.Nature communications · 2026Article
- Review
- RNA helicase SKIV2L impedes tumor immunity by reprogramming arginine metabolism of hepatocellular carcinomas.Journal for immunotherapy of cancer · 2026Article
- Effective therapeutic targeting of CTNNB1-mutant hepatoblastoma with WNTinib.Molecular oncology · 2026Article
- Targeting p38α in cancer: challenges, opportunities, and emerging strategies.Molecular oncology · 2026Review
- Targeting circGDI2 disrupt HNRNPC-mediated mPORCN stabilization and enhance LGK-974 anti-tumor therapy in hepatocellular carcinoma.Molecular cancer · 2026Article
- WNT-β-catenin signalling in hepatocellular carcinoma: from bench to clinical trials.Nature reviews. Gastroenterology & hepatology · 2026Review
- Global trend of organoid implementation for hepatocellular carcinoma research (2005-2024): bibliometric analysis.Przeglad gastroenterologiczny · 2026Article
- WT1 gene: a potential therapeutic target for multiple cancer treatment strategies.Clinical and experimental medicine · 2025Review
- Precision targeting of β-catenin induces tumor reprogramming and immunity in hepatocellular cancers.Nature communications · 2025Article
- Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Precision models in hepatocellular carcinoma.Nature reviews. Gastroenterology & hepatology · 2025Review
- Mitochondrial metabolism: A moving target in hepatocellular carcinoma therapy.Journal of cellular physiology · 2025Review
- Development of mutated β-catenin gene signature to identifyJHEP reports : innovation in hepatology · 2024Article
Corrections and comments
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Authors and funding
35 authors at 10 institutions in 3 countries.
Alex Rialdi *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.
Mary Duffy *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.
Alex P Scopton *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.
Frank FonsecaCenter for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Julia Nanyi ZhaoCenter for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0002-4352-7748
Megan SchwarzCenter for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Pedro Molina-SanchezDepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Slim MzoughiCenter for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Elisa ArceciCenter for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Jordi Abril-FornagueraGraduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0002-5871-4052
Austin MeadowsCenter for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Marina Ruiz de GalarretaDepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Denis TorreCenter for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Kyna ReyesCenter for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Yan Ting LimInstitute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
Felix RosemannDepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0002-1649-3247
Zaigham M KhanCenter for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0002-2471-4054
Kevin MohammedCenter for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Xuedi WangBioinformatics for Next Generation Sequencing Shared Resource Facility, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Xufen YuCenter for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0001-7794-7890
Manikandan LakshmananInstitute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
Ravisankar RajarethinamInstitute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.ORCID 0000-0001-9249-7840
Soo Yong TanInstitute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
Jian JinCenter for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0002-2387-3862
Augusto VillanuevaLiver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0003-3585-3727
Eleftherios MichailidisLaboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.ORCID 0000-0002-9907-4346
Ype P De JongLaboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
Charles M RiceLaboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
Ivan MarazziDepartment of Biological Cancer, University of California Irvine, Orange, CA, USA.
Dan HassonBioinformatics for Next Generation Sequencing Shared Resource Facility, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Josep M LlovetLiver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0003-0547-2667
Radoslaw M SobotaInstitute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.ORCID 0000-0002-2455-2526
Amaia LujambioDepartment of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. amaia.lujambio@mssm.edu.ORCID 0000-0002-2798-1481
Ernesto Guccione *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.ORCID 0000-0001-7764-5307
Arvin C Dar *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.ORCID 0000-0003-0318-4848
Icahn School of Medicine at Mount Sinai · USTisch Hospital · USAgency for Science, Technology and Research · SGConsorci Institut D'Investigacions Biomediques August Pi I Sunyer · ESCornell University · USEmory University · USInstitució Catalana de Recerca i Estudis Avançats · ESMemorial Sloan Kettering Cancer Center · USRockefeller University · USUniversity of California, Irvine · US
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MTHE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANTP30CA196521 · NCI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Ramon E Parsons · 2015 to 2026
$35.4MTRAINING PROGRAM IN CANCER THERAPYT32CA078207 · NCI · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI James J Manfredi · 1999 to 2026
$11.6MTeaching biomedical and pharmacological trainees to produce FAIR data for AI & ML applicationsT32GM062754 · NIGMS · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI SCHLESSINGER, AVNER · 2001 to 2023
$6.2MTargeting Oncogenic Ras-MAPK Signaling Complexes via the Scaffold KSRR01CA227636 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI Arvin Dar · 2018 to 2026
$4.0MAN INTEGRATED PLATFORM FOR NOVEL PERSONALIZED LIVER CANCER THERAPEUTICSR01CA256480 · NCI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI DAR, ARVIN, GUCCIONE, ERNESTO · 2021 to 2025
$3.3MDissecting and targeting canonical and non-canonical oncogenic functions of EZH2 in canerR01CA268519 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Jian Jin, G Greg Wang · 2022 to 2026
$3.2MA Chemical Genetic Approach to Exploring Novel Therapeutic Space for Colorectal CancerR01CA258736 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI DAR, ARVIN · 2021 to 2025
$3.2MIn search of an HBV cure: novel model systems and targetsR01AI143295 · NIAID · ROCKEFELLER UNIVERSITY · PI RICE, CHARLES M · 2019 to 2023
$3.0MTargeting Lysine Methyltransferases EZH2 and EZH1 for Treating MLL-rearranged LeukemiasR01CA218600 · NCI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI JIN, JIAN, WANG, G GREG · 2017 to 2021
$2.8MTumor-intrinsic signaling pathways restrict anti-tumor immunity in hepatocellular carcinomaR37CA230636 · NCI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI LUJAMBIO, AMAIA · 2018 to 2024
$2.7MTargeting Ras-Dependent Cancers with a Chemical Switch for an Inactive KinaseDP2CA186570 · NCI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI DAR, ARVIN · 2013 to 2017
$2.7MCancer Research UK 26813NCI NIH HHS DP2 CA186570NCI NIH HHS F32 CA247414NCI NIH HHS K99 CA273538NCI NIH HHS P30 CA008748NCI NIH HHS P30 CA196521NCI NIH HHS R01 CA218600NCI NIH HHS R01 CA227636NCI NIH HHS R01 CA230854NCI NIH HHS R01 CA256480NCI NIH HHS R01 CA258736NCI NIH HHS R01 CA268519NCI NIH HHS R37 CA230636NCI NIH HHS T32 CA078207NIAAA NIH HHS R01 AA027327NIAID NIH HHS R01 AI143295NIDDK NIH HHS R01 DK128289NIGMS NIH HHS T32 GM062754NIH HHS S10 OD025132NIH HHS S10 OD028504
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.
Indexed as
Antineoplastic AgentsCarcinoma, HepatocellularLiver NeoplasmsAnimalsbeta CateninHumansMiceProtein Kinase InhibitorsTranscription FactorsAntineoplastic Agentsbeta CateninProtein Kinase InhibitorsTranscription Factors
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