Scholarlink

<p>Cetuximab resistance remains a major obstacle in the treatment of metastatic colorectal cancer (mCRC), highlighting the urgent need to identify synthetic lethal partners of EGFR. In this study, we observed glutamate dehydrogenase 1 (GDH1) accumulation in cetuximab-treated CRC samples. GDH1 depletion sensitized CRC cells to cetuximab and suppressed remodeling of the tumor immune microenvironment (TIME), as revealed by single-cell RNA sequencing. Mechanistically, cetuximab treatment induced substantial cytosolic accumulation of GDH1. Under normal conditions, EGFR directly phosphorylates cytosolic GDH1 at Y451, leading to HIP1R-mediated lysosomal degradation. Cetuximab, however, blocks GDH1-Y451 phosphorylation, thereby stabilizing GDH1 and increasing α-ketoglutarate (αKG) production. Elevated αKG enhances ALKBH5 activity to demethylate m6A modifications in the 3′UTR of <i>NDUFA2</i>, <i>CXCL3</i>, and <i>SOS1</i> pre-mRNAs. This cascade coordinately rewires tumor cell metabolism and reprograms the TIME, while also amplifying KRAS-driven signaling to promote CRC liver metastasis. Importantly, combining cetuximab with the GDH1 activity inhibitor R162 curbed tumor metabolic adaptation, reversed TIME remodeling, and suppressed KRAS activation, thereby preventing immune escape and metastatic progression. Our findings unveil the EGFR/GDH1/αKG/ALKBH5 axis as a key modulator of cetuximab response and suggest that post-treatment monitoring of blood αKG may help identify patients who could benefit from GDH1 inhibition to augment immunotherapy and KRAS-targeted strategies.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

α-ketoglutarate accumulation orchestrates immunosuppressive metabolic remodeling to drive cetuximab resistance in metastatic colorectal cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月30日

查看全文
  • Yingwei Zhu,
  • Kuijie Liu,
  • Ling Chang,
  • Jian Lu,
  • Hong Tang,
  • Zhenxin Zhu,
  • Zhiru Chen,
  • Xiongjun Wang,
  • Jing Xiao

摘要

Cetuximab resistance remains a major obstacle in the treatment of metastatic colorectal cancer (mCRC), highlighting the urgent need to identify synthetic lethal partners of EGFR. In this study, we observed glutamate dehydrogenase 1 (GDH1) accumulation in cetuximab-treated CRC samples. GDH1 depletion sensitized CRC cells to cetuximab and suppressed remodeling of the tumor immune microenvironment (TIME), as revealed by single-cell RNA sequencing. Mechanistically, cetuximab treatment induced substantial cytosolic accumulation of GDH1. Under normal conditions, EGFR directly phosphorylates cytosolic GDH1 at Y451, leading to HIP1R-mediated lysosomal degradation. Cetuximab, however, blocks GDH1-Y451 phosphorylation, thereby stabilizing GDH1 and increasing α-ketoglutarate (αKG) production. Elevated αKG enhances ALKBH5 activity to demethylate m6A modifications in the 3′UTR of NDUFA2, CXCL3, and SOS1 pre-mRNAs. This cascade coordinately rewires tumor cell metabolism and reprograms the TIME, while also amplifying KRAS-driven signaling to promote CRC liver metastasis. Importantly, combining cetuximab with the GDH1 activity inhibitor R162 curbed tumor metabolic adaptation, reversed TIME remodeling, and suppressed KRAS activation, thereby preventing immune escape and metastatic progression. Our findings unveil the EGFR/GDH1/αKG/ALKBH5 axis as a key modulator of cetuximab response and suggest that post-treatment monitoring of blood αKG may help identify patients who could benefit from GDH1 inhibition to augment immunotherapy and KRAS-targeted strategies.