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

Alex Rialdi, Mary Duffy, Alex P. Scopton, Frank Fonseca, Julia Nanyi Zhao, Megan Schwarz, Pedro Molina-Sanchez, Slim Mzoughi, Elisa Arceci, Jordi Abril-Fornaguera, Austin Meadows, Marina Ruiz de Galarreta, Denis Torre, Kyna Reyes, Yan Ting Lim, Felix Rosemann, Zaigham M. Khan, Kevin Mohammed, Xuedi Wang, Xufen YuManikandan Lakshmanan, Ravisankar Rajarethinam, Soo Yong Tan, Jian Jin, Augusto Villanueva, Eleftherios Michailidis, Ype P. De Jong, Charles M. Rice, Ivan Marazzi, Dan Hasson, Josep M. Llovet, Radoslaw M. Sobota, Amaia Lujambio, Ernesto Guccione, Arvin C. Dar

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Pages (from-to)1157-1175
Number of pages19
JournalNature Cancer
Volume4
Issue number8
DOIs
StatePublished - Aug 2023

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