PO.BCS01.10 · 生物信息与计算
KRAS信号转导的多组学解析揭示了结直肠癌中可靶向的代谢和DNA修复脆弱性
Multiomic dissection of KRAS signaling reveals targetable metabolic and DNA repair vulnerabilities in colorectal cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：KRAS是结直肠癌中最常见的致癌驱动因素之一，历来被认为是"不可成药的"；然而，直接的KRAS抑制剂如今正进入临床试验。KRAS调控的系统层面效应仍未得到充分表征，限制了治疗见解。我们应用整合多组学分析来揭示可增强转化策略的机制性脆弱性。
方法：对同源HCT-116结直肠癌细胞（纯合KRAS^G13D突变 vs. 部分KRAS缺失）进行生物学重复分析（n = 3-5），涵盖转录组学（15,432个基因）、蛋白质组学（6,654种蛋白）、磷酸化蛋白质组学（10,034个磷酸肽）和代谢组学（3,015种代谢物）。多层数据（>30,000个分析物）通过通路富集、相关性网络和降维进行整合，以识别KRAS下游的核心分子模块。
结果：KRAS缺失产生了广泛的分子重编程：640个转录本、74种蛋白、744个磷酸肽和519种代谢物显示出显著变化（q<0.05）。代谢组学受扰动最大（>17%），显示线粒体呼吸和支链氨基酸分解代谢增加，同时糖酵解受到抑制。下调的信号包括胶原生物合成、EGFR、IGF转运和IL-4/IL-13通路。网络整合将>30,000个特征提炼为<100个分子模块，凸显了缩醛磷脂相关脂质重塑中的代谢转变，以及核孔、核糖体和DNA修复蛋白（ATRX、DAXX）磷酸化的改变。这些发现表明在氧化代谢、脂质代谢、核糖体生物发生和基因组稳定性方面存在脆弱性。
结论：这项全面的多组学分析揭示，KRAS驱动的结直肠癌依赖于对代谢、细胞外基质信号和DNA修复通路的协调控制。KRAS减弱使细胞转向氧化代谢，同时暴露出脂质代谢和DNA修复机制中的脆弱性。这些发现提示，将KRAS抑制与代谢或DNA损伤靶向疗法相结合的组合治疗策略。
查看英文原文 English abstract
Background: KRAS is among the most common oncogenic drivers in colorectal cancer and is historically “undruggable”; yet direct KRAS inhibitors are now entering clinical trials. The systems-level effects of KRAS modulation remain poorly characterized, limiting therapeutic insights. We applied integrated multiomic profiling to reveal mechanistic vulnerabilities that could enhance translational strategies.
Methods: Isogenic HCT-116 colorectal carcinoma cells (homozygous KRAS^G13D mutation vs. partial KRAS loss) were analyzed in biological replicates (n = 3-5) across transcriptomics (15,432 genes), proteomics (6,654 proteins), phosphoproteomics (10,034 phosphopeptides), and metabolomics (3,015 metabolites). Multi-layer data (>30,000 analytes) were integrated via pathway enrichment, correlation networks, and dimensionality reduction to identify core molecular modules downstream of KRAS.
Results: KRAS deletion produced broad molecular reprogramming: 640 transcripts, 74 proteins, 744 phosphopeptides, and 519 metabolites showed significant changes (q<0.05). Metabolomics was most perturbed (>17%), revealing increased mitochondrial respiration and branched-chain amino acid catabolism, alongside suppressed glycolysis. Downregulated signaling included collagen biosynthesis, EGFR, IGF transport, and IL-4/IL-13 pathways. Network integration distilled >30,000 features into <100 molecular modules, highlighting metabolic shifts in plasmalogen-associated lipid remodeling and altered phosphorylation of nuclear pore, ribosomal, and DNA repair proteins (ATRX, DAXX). These findings indicate vulnerabilities in oxidative metabolism, lipid metabolism, ribosome biogenesis, and genome stability.
Conclusions: This comprehensive multiomic analysis reveals that KRAS-driven colorectal cancer depends on coordinated control of metabolism, extracellular matrix signaling, and DNA repair pathways. KRAS attenuation shifts cells to oxidative metabolism while exposing vulnerabilities in lipid metabolism and DNA repair machinery. These findings suggest combinatorial therapeutic strategies integrating KRAS inhibition with metabolic or DNA damage-targeted therapies.
利益披露 Disclosure
T. Cohen, None..
A. Mehta, None..
A. Richardson, None..
M. Gandhi, None..
D. Guzior, None..
K. Cho, None..
E. Stancliffe, None.