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

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Acta Pharmacologica Sinica Pub Date : 2024-11-06 DOI:10.1038/s41401-024-01409-2
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
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Abstract

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.

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NPPS 的依赖性为 RAS 突变癌症提供了可瞄准的弱点。
RAS 是最常发生突变的致癌蛋白。了解 RAS 的生物学特性并发现 RAS 通路中可药物治疗的关键环节,是对 RAS 突变癌症进行靶向治疗的先决条件。最近发现的 KRASG12C 抑制剂打破了 RAS "不可药用 "的魔咒,改变了 KRAS 突变癌症的治疗模式。然而,KRAS突变(更不用说KRASG12C突变)只占RAS突变癌症的一部分。针对携带其他 RAS 突变的癌症的靶向疗法仍是当务之急。在这项研究中,我们探索了能够广泛抑制 RAS 突变体的关键调控分子。通过比较核苷酸焦磷酸酶(NPPS)在一组细胞系中的表达水平以及 NPPS 在 RAS 突变细胞中表达增加的功能性后果,我们证明了具有各种 RAS 突变的癌细胞的生长和存活依赖于 NPPS,而这种依赖性使 RAS 突变癌症易受 NPPS 抑制治疗的影响。与RAS野生型细胞相比,RAS突变细胞对NPPS的上调感到厌烦和需要。转录组学和代谢组学分析表明,RAS 突变细胞中存在依赖 NPPS 的高糖酵解。我们证明,NPPS 通过加强与催化糖酵解第一步的酶 hexokinase 1(HK1)的相互作用,促进了 RAS 突变细胞中葡萄糖衍生的糖酵解中间产物。使用 NPPS 抑制剂 Enpp-1-IN-1 或 HK1 抑制剂 2-脱氧葡萄糖(2-DG)对 NPPS-HK1 轴进行药理抑制,或对 NPPS 进行基因干扰,可抑制体外和体内的 RAS 突变癌症。总之,这项研究揭示了一种尚未认识到的泛互补-RAS通路调节机制和可药物治疗的关键,为治疗RAS突变癌症提出了一种新的潜在治疗方法。
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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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