文章目录

wntininib是一种多激酶抑制剂，对β-catenin突变型肝细胞癌具有特异性

原文发布日期：2023-08-03

英文摘要：

摘要翻译：

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文章：

wntininib是一种多激酶抑制剂，对β-catenin突变型肝细胞癌具有特异性

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

原文发布日期：2023-08-03

英文摘要：

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.

摘要翻译：

肝细胞癌（HCC）是全球癌症死亡的主要原因之一。β-半脱氧核苷酸互换性状的HCC占这种疾病案例的30%，但目前尚未有精准治疗方法。基于临床多激酶抑制剂骨架中提取的化学库，我们筛选出HCC器官样体，从而鉴定出WNTinib这一具有选择性（在CTNNB1突变的人类及小鼠模型，包括病人的样本）的KIT抑制剂。通过结合多组学分析、靶点结合实验、补救实验以及体内外疗效研究，我们发现，WNTinib比现有的临床激酶抑制剂更有效，并且同时能抑制KIT和MAPK信号通路的多个节点。