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

• DOI: 10.1038/s41401-024-01409-2
• Publication Date: 2024-11-06T09:04:36Z
• Authors: 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
• Keywords: Targeted Therapy

Abstract RAS is the most frequently mutated oncoprotein for cancer driving. Understanding of biology and discovery druggable lynchpins in pathway a prerequisite targeted therapy RAS-mutant cancers. The recent identification KRAS G12C inhibitor breaks “undruggable” curse on has changed paradigm KRAS-mutant However, mutations, let alone mutation, account only part RAS-mutated Targeted therapies cancers harboring other mutations remain urgent need. In this study we explored pivotal regulatory molecules that allow broad inhibition mutants. By comparing expression levels nucleotide pyrophosphatase (NPPS) panel cell lines functional consequence increased NPPS cells, demonstrated cells with various kinds depended growth survival, dependence conferred vulnerability to treatment inhibition. compared RAS-wildtype bored required an upregulation NPPS. Transcriptomics metabolomics analyses revealed NPPS-dependent hyperglycolysis cells. We promoted glucose-derived glycolytic intermediates by enhancing its interaction hexokinase 1 (HK1), enzyme catalyzing first committed step glycolysis. Pharmacological NPPS-HK1 axis using Enpp-1-IN-1 or HK1 2-deoxyglucose (2-DG), genetic interfere suppressed vitro vivo. conclusion, reveals unrecognized mechanism lynchpin modulation pan-mutant-RAS pathway, proposing new potential therapeutic approach treating