2. Academic Validation
  3. WNTinib is a multi-kinase inhibitor with specificity against β-catenin mutant hepatocellular carcinoma

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

  • Nat Cancer. 2023 Aug;4(8):1157-1175. doi: 10.1038/s43018-023-00609-9.
Alex Rialdi # 1 2 3 4,  Mary Duffy # 1 5,  Alex P Scopton # 1,  Frank Fonseca 1 4 5,  Julia Nanyi Zhao 1 2 3 4 5,  Megan Schwarz 1 2 3 4 5,  Pedro Molina-Sanchez 2 3 6,  Slim Mzoughi 1 2 4,  Elisa Arceci 1 2 4 5,  Jordi Abril-Fornaguera 5 7,  Austin Meadows 1 2 4,  Marina Ruiz de Galarreta 2 3 6,  Denis Torre 1 2 3 4 5,  Kyna Reyes 1 2,  Yan Ting Lim 8,  Felix Rosemann 2 5,  Zaigham M Khan 1,  Kevin Mohammed 1 4 9,  Xuedi Wang 10,  Xufen Yu 1,  Manikandan Lakshmanan 8,  Ravisankar Rajarethinam 8,  Soo Yong Tan 8 11,  Jian Jin 1,  Augusto Villanueva 3 12,  Eleftherios Michailidis 13 14,  Ype P De Jong 13 15,  Charles M Rice 13,  Ivan Marazzi 16,  Dan Hasson 10,  Josep M Llovet 3 7 17,  Radoslaw M Sobota 8,  Amaia Lujambio 18 19 20 21,  Ernesto Guccione # 22 23 24 25 26 27,  Arvin C Dar # 28 29 30
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3 Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4 Center for OncoGenomics and Innovative Therapeutics, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5 Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 6 The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 7 Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain.
  • 8 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
  • 9 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, USA.
  • 10 Bioinformatics for Next Generation Sequencing Shared Resource Facility, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 11 Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 12 Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 13 Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
  • 14 Laboratory of Biochemical Pharmacology, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA.
  • 15 Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA.
  • 16 Department of Biological Cancer, University of California Irvine, Orange, CA, USA.
  • 17 Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
  • 18 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. amaia.lujambio@mssm.edu.
  • 19 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.
  • 20 Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. amaia.lujambio@mssm.edu.
  • 21 The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. amaia.lujambio@mssm.edu.
  • 22 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.
  • 23 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernesto.guccione@mssm.edu.
  • 24 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.
  • 25 Center for OncoGenomics and Innovative Therapeutics, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernesto.guccione@mssm.edu.
  • 26 The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernesto.guccione@mssm.edu.
  • 27 Bioinformatics for Next Generation Sequencing Shared Resource Facility, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernesto.guccione@mssm.edu.
  • 28 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.
  • 29 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. dara1@mskcc.org.
  • 30 Program in Chemical Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. dara1@mskcc.org.
  • # Contributed equally.
PMID: 37537299 DOI: 10.1038/s43018-023-00609-9
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.

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