PO.MCB09.06 · 分子与细胞生物学
基于KRAS状态靶向NRF2调控的多胺和谷胱甘肽代谢可增强结直肠癌的化疗疗效
Targeting NRF2-regulated polyamine and glutathione metabolism enhances chemotherapy efficacy in colorectal cancer based on KRAS status
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摘要 Abstract
中文摘要
代谢重编程是结直肠癌的一个标志，并受致癌性KRAS突变的强烈影响，后者导致药物反应性降低和临床结局不佳。诱导铁死亡——一种铁依赖性、脂质过氧化驱动的细胞死亡形式——已成为通过破坏这种适应性代谢状态来增强化疗反应的一种有前景的策略。然而，KRAS特异性代谢与铁死亡诱导的药物敏感性之间的相互作用仍未被充分理解，而阐明这一点可能实现精准治疗干预。在本研究中，我们整合了公共数据集和体外实验，以探究药物联合效应以及代谢将如何被改变。我们首先利用CRC细胞系的药物敏感性数据，发现药物反应因KRAS状态而异，并涉及不同的铁死亡依赖性：KRAS突变型细胞对铁处理相关基因（FTH1、FTL、SLC11A2）的依赖性增加，而KRAS野生型细胞对GPX4介导的抗氧化防御的破坏更为脆弱。鉴于NRF2通过铁稳态和抗氧化反应共同协调铁死亡，使用Brusatol对四种CRC细胞系（代表野生型、KRAS G12D和KRAS G13D）进行NRF2的药理学抑制显著增强了化疗疗效，其中在KRAS G12D细胞系中观察到最强的效应，其次是野生型细胞。在非靶向代谢组学分析方面，Brusatol与Oxaliplatin或5-Fluorouracil联合处理仅在野生型细胞和KRAS G12D突变型中使驱动癌症生长和进展的通路失调，包括甲硫氨酸循环、核苷酸合成以及能量代谢，这解释了抑制效应的改善。此外，在这种联合治疗下观察到取决于KRAS突变的独特改变，表现为KRAS突变体（包括KRAS G12D和KRAS G13D）显示出多胺分解代谢的阻断，乙酰精胺极度降低，而野生型细胞则遭受氧化应激升高，伴随严重的GSH耗竭和GSH/GSSG比值降低。鉴于Brusatol在临床上的不可及性，我们利用基于转录的计算机药物重定位方法，成功地重新定位了几种临床可行的抗肿瘤药物以及一组处于临床前状态的治疗剂用于新兴的肿瘤对抗。我们的发现凸显了NRF2剥夺介导的多胺代谢作为化疗增敏的潜在靶点，并为KRAS G12D CRC提供了一种临床批准的治疗选择，为靶向治疗和转化医学照亮了道路。
查看英文原文 English abstract
Metabolic reprogramming is a hallmark of colorectal cancer and is strongly influenced by oncogenic KRAS mutations, which contributes to reduced drug responsiveness and poor clinical outcomes. Inducing ferroptosis-a form of iron-dependent, lipid peroxidation-driven cell death-has emerged as a promising strategy to augment chemotherapy response by disrupting this adaptive metabolic state. However, the interplay between KRAS-specific metabolism and ferroptosis-induced drug sensitivity remains incompletely understood and could enable precision therapeutic interventions. In our study, we integrated public datasets and in vitro experiments to investigate the drug combination effect and how the metabolism will be altered. We first utilized drug sensitivity data from CRC cell lines, and we found that drug response varied by KRAS status and engaged distinct ferroptotic dependencies: KRAS-mutant cells showed increased reliance on iron-handling genes ( FTH1, FTL, SLC11A2 ), whereas KRAS wild-type cells were more vulnerable to disruption of GPX4-mediated antioxidant defense. Given that NRF2 coordinates ferroptosis through both iron homeostasis and antioxidant responses, pharmacologic inhibition of NRF2 using Brusatol across four CRC cell lines (representing wild type, KRAS G12D, and KRAS G13D) markedly enhanced chemotherapy efficacy, with the strongest effect observed in KRAS G12D lines, followed by wild-type cells. Regarding non-targeted metabolomics analysis, co-treatment with Brusatol and Oxaliplatin or 5-Fluorouracil rendered dysregulated pathways that fuel cancer growth and progression, including methionine cycle, nucleotide synthesis as well as energy metabolism only in wild-type cells and KRAS G12D mutant which accounted for improved inhibitory effect. Moreover, distinctive alterations depending on KRAS mutation were observed under this combination therapy, manifesting KRAS mutants (comprising KRAS G12D and KRAS G13D ) demonstrated an blockage of polyamine catabolism with extremely decreased acetylspermine, whereas wild-type cells suffered elevated oxidative stress with severe GSH exhaustion and GSH/GSSG ratio reduction. In light of clinical unavailability of Brusatol, we successfully repositioned several clinically viable antineoplastic drugs and a panel of therapeutic agents under preclinical status for emerging tumor combat utilizing a transcriptional-based silico drug repurposing approach. Our findings highlighted NRF2 deprivation-mediated polyamine metabolism as a potential target for chemosensitivity and provided a clinically-approved therapeutic option in KRAS G12D CRC, brightening the path for targeted therapy and translation medicine.
利益披露 Disclosure
J. Li, None..
J. Feng, None..
F. Wang, None..
Y. Zhang, None..
H. Yan, None..
Z. Cai, None.