Dependence of NPPS creates a targetable vulnerability in RAS-mutant cancers  

作　　者：Rui-xue Xia Pei-chen Zou Jun-ting Xie Ya-bin Tang Miao-miao Gong Fu Fan Ayinazhaer Aihemaiti Yu-qing Liu Ying Shen Bin-bing S.Zhou Liang Zhu Hui-min Lei 

机构地区：[1]Key Laboratory of Pediatric Hematology and Oncology Ministry of Health,Pediatric Translational Medicine Institute,Shanghai Children’s Medical Center,Shanghai Jiao Tong University School of Medicine,Shanghai,200127,China [2]Department of Pharmacology and Chemical Biology,College of Basic Medical Sciences,Shanghai Jiao Tong University School of Medicine,Shanghai,200025,China

出　　处：《Acta Pharmacologica Sinica》2025年第3期728-739,共12页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(No.82273950 and No.82003772).

摘　　要：RAS is the most frequently mutated oncoprotein for cancer driving.Understanding of RAS biology and discovery of druggable lynchpins in RAS pathway is a prerequisite for targeted therapy of RAS-mutant cancers.The recent identification of KRASG12C inhibitor breaks the“undruggable”curse on RAS and has changed the therapy paradigm of KRAS-mutant cancers.However,KRAS mutations,let alone KRASG12C mutation,account for only part of RAS-mutated cancers.Targeted therapies for cancers harboring other RAS mutations remain the urgent need.In this study we explored the pivotal regulatory molecules that allow for broad inhibition of RAS mutants.By comparing the expression levels of nucleotide pyrophosphatase(NPPS)in a panel of cell lines and the functional consequence of increased NPPS expression in RAS-mutant cells,we demonstrated that cancer cells with various kinds of RAS mutations depended on NPPS for growth and survival,and that this dependence conferred a vulnerability of RAS-mutant cancer to treatment of NPPS inhibition.RAS-mutant cells,compared with RAS-wildtype cells,bored and required an upregulation of NPPS.Transcriptomics and metabolomics analyses revealed a NPPS-dependent hyperglycolysis in RAS-mutant cells.We demonstrated that NPPS promoted glucose-derived glycolytic intermediates in RAS-mutant cells by enhancing its interaction with hexokinase 1(HK1),the enzyme catalyzing the first committed step of glycolysis.Pharmacological inhibition of NPPS-HK1 axis using NPPS inhibitor Enpp-1-IN-1 or HK1 inhibitor 2-deoxyglucose(2-DG),or genetic interfere with NPPS suppressed RAS-mutant cancers in vitro and in vivo.In conclusion,this study reveals an unrecognized mechanism and druggable lynchpin for modulation of pan-mutant-RAS pathway,proposing a new potential therapeutic approach for treating RAS-mutant cancers.

关 键 词：RAS-mutantcancers NPPS HK1 GLYCOLYSIS 

分 类 号：R730.2[医药卫生—肿瘤]