上海交通大学Hui-min Lei等研究人员合作发现，NPPS的依赖性在RAS突变癌症中创造了一个可靶向的脆弱性。该研究于2024年11月6日在线发表于国际一流学术期刊《中国药理学报》。

研究人员探索了可广泛抑制RAS突变的关键调控分子。通过比较细胞系中核苷酸焦磷酸酶（NPPS）的表达水平，并研究在RAS突变细胞中NPPS表达增加的功能后果，研究人员证明了具有各种RAS突变的癌细胞依赖于NPPS的生长和存活，并且这种依赖性使得RAS突变癌症对NPPS抑制治疗具有脆弱性。

与RAS野生型细胞相比，RAS突变细胞更需要并且会上调NPPS的表达。转录组学和代谢组学分析揭示了RAS突变细胞中NPPS依赖的高糖酵解现象。

研究人员证明，NPPS通过增强其与己糖激酶1（HK1）的相互作用可促进RAS突变细胞中的葡萄糖来源的糖酵解中间体，HK1是催化糖酵解第一步的酶。使用NPPS抑制剂Enpp-1-IN-1或HK1抑制剂2-脱氧葡萄糖（2-DG）进行药理学抑制NPPS-HK1通路，或通过基因干预NPPS，均能抑制RAS突变癌症的体外和体内生长。

总之，该研究揭示了一种未被认识的机制和可靶向的关键分子，调节了全突变RAS通路，提出了一种治疗RAS突变癌症的新潜在治疗方法。

据悉，RAS是最常见的癌症驱动突变蛋白之一。理解RAS生物学及其在RAS通路中的药物靶点发现是RAS突变癌症靶向治疗的前提。最近KRAS^G12C抑制剂的发现打破了RAS的“无法靶向”诅咒，改变了KRAS突变癌症的治疗范式。然而，KRAS突变，更不用说KRAS^G12C突变，仅占RAS突变癌症的一部分。针对其他RAS突变的靶向治疗仍然是急需解决的问题。

附：英文原文

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

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

Issue&Volume: 2024-11-06

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.

DOI: 10.1038/s41401-024-01409-2

Source: https://www.nature.com/articles/s41401-024-01409-2