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Ref Type Journal Article
PMID (37537299)
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, Ruiz de Galarreta M, Torre D, Reyes K, Lim YT, Rosemann F, Khan ZM, Mohammed K, Wang X, Yu X, 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
Title WNTinib is a multi-kinase inhibitor with specificity against β-catenin mutant hepatocellular carcinoma.
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
WNTinib WNTinib 12 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
WNTinib FLT3 Inhibitor 68 KIT Inhibitor 57 PDGFR Inhibitor (Pan) 30 RET Inhibitor 52 VEGFR1 Inhibitor 6 VEGFR2 Inhibitor 37 WNTinib is a multi-kinase inhibitor with activity against KIT, PDGFRA/B, VEGFR1/2, RET, and FLT3, which potentially decreases tumor growth and has selectivity for CTNNB1-mutant tumors (PMID: 37537299).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CTNNB1 S37F CTNNB1 S45Y hepatocellular carcinoma sensitive WNTinib Preclinical - Patient cell culture Actionable In a preclinical study, WNTinib inhibited Ezh2 phosphorylation and viability in a patient-derived hepatocellular carcinoma cell line harboring CTNNB1 S37F and S45Y in culture (PMID: 37537299). 37537299
CTNNB1 mut KIT V559D KIT T670I hepatocellular carcinoma predicted - sensitive WNTinib Preclinical - Cell culture Actionable In a preclinical study, a hepatocellular carcinoma cell line harboring a deletion of CTNNB1 exons and expressing KIT V559D and T670I was resistant to WNTinib in culture (PMID: 37537299). 37537299
CTNNB1 S37C hepatocellular carcinoma sensitive WNTinib Preclinical - Cell culture Actionable In a preclinical study, WNTinib inhibited Ezh2 phosphorylation and viability in a hepatocellular carcinoma cell line harboring CTNNB1 S37C in culture (PMID: 37537299). 37537299
CTNNB1 S45F hepatocellular carcinoma sensitive WNTinib Preclinical - Patient cell culture Actionable In a preclinical study, WNTinib inhibited Ezh2 phosphorylation and viability in a patient-derived hepatocellular carcinoma cell line harboring CTNNB1 S45F in culture (PMID: 37537299). 37537299
CTNNB1 G34V hepatocellular carcinoma sensitive WNTinib Preclinical - Cell culture Actionable In a preclinical study, WNTinib inhibited Ezh2 phosphorylation and viability in a hepatocellular carcinoma cell line harboring CTNNB1 G34V in culture (PMID: 37537299). 37537299
CTNNB1 S45P hepatocellular carcinoma sensitive WNTinib Preclinical - Patient cell culture Actionable In a preclinical study, WNTinib inhibited Ezh2 phosphorylation and viability in patient-derived hepatocellular carcinoma cell lines harboring CTNNB1 S45P in culture (PMID: 37537299). 37537299
BRAF T529N CTNNB1 mut hepatocellular carcinoma predicted - sensitive WNTinib Preclinical - Cell culture Actionable In a preclinical study, WNTinib inhibited viability in a hepatocellular carcinoma cell line harboring a deletion of CTNNB1 exons and expressing BRAF T529N in culture (PMID: 37537299). 37537299
CTNNB1 T41A hepatocellular carcinoma sensitive WNTinib Preclinical - Patient cell culture Actionable In a preclinical study, WNTinib inhibited Ezh2 phosphorylation and viability in patient-derived hepatocellular carcinoma cell lines harboring CTNNB1 T41A in culture (PMID: 37537299). 37537299
CTNNB1 mut MAP2K1 S218D MAP2K1 S222D hepatocellular carcinoma predicted - resistant WNTinib Preclinical - Cell culture Actionable In a preclinical study, a hepatocellular carcinoma cell line harboring a deletion of CTNNB1 exons and expressing MAP2K1 S218D and S222D was resistant to WNTinib in culture (PMID: 37537299). 37537299
CTNNB1 S33F hepatocellular carcinoma sensitive WNTinib Preclinical - Patient cell culture Actionable In a preclinical study, WNTinib inhibited Ezh2 phosphorylation and viability in a patient-derived hepatocellular carcinoma cell line harboring CTNNB1 S33F in 2D and 3D culture (PMID: 37537299). 37537299
CTNNB1 act mut hepatocellular carcinoma sensitive WNTinib Preclinical Actionable In a preclinical study, WNTinib increased survival in a mouse model of CTNNB1-driven hepatocellular carcinoma (PMID: 37537299). 37537299
CTNNB1 mutant hepatocellular carcinoma predicted - sensitive WNTinib Preclinical - Cell culture Actionable In a preclinical study, WNTinib inhibited Ezh2 phosphorylation and viability in a hepatocellular carcinoma cell line harboring a deletion of CTNNB1 exons in culture (PMID: 37537299). 37537299