Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature cancer			2023 Aug 03		Nat Cancer

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 69 KIT Inhibitor 57 PDGFR Inhibitor (Pan) 30 RET Inhibitor 53 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
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 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 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 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
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 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 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 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 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 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 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 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