RecurrentFBXW7mutations bypass Wnt/β-catenin addiction in cancer

Author:

Zhong ZhengORCID,Virshup David M.ORCID

Abstract

AbstractPathologic Wnt/β-catenin signaling drives various cancers, leading to multiple approaches to drug this pathway. Appropriate patient selection can maximize success of these interventions. Wnt ligand addiction is a druggable vulnerability inRNF43-mutant/RSPO-fusion cancers. However, pharmacologically targeting the biogenesis of Wnt ligands, e.g., with PORCN inhibitors, has shown mixed therapeutic responses, possibly due to tumor heterogeneity. Here we show that the tumor suppressorFBXW7is frequently mutated inRNF43-mutant/RSPO-fusion tumors, andFBXW7mutations cause intrinsic resistance to anti-Wnt therapies. Mechanistically, inactivation of FBXW7 stabilizes multiple oncoproteins including Cyclin E and MYC, and antagonizes the cytostatic effect of Wnt inhibitors. Moreover, althoughFBXW7mutations do not mitigate β-catenin degradation upon Wnt inhibition,FBXW7-mutantRNF43-mutant/RSPO-fusion cancers instead lose dependence on β-catenin signaling, accompanied by dedifferentiation and loss of lineage specificity. TheseFBXW7-mutant Wnt/β-catenin-independent tumors are susceptible to multi-CDK inhibition by dinaciclib. An in depth understanding of primary resistance to anti-Wnt/β-catenin therapies allows for more appropriate patient selection and use of alternative mechanism-based therapies.

Publisher

Cold Spring Harbor Laboratory

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3