Scholarlink

<p>Anti-EGFR monoclonal antibodies are essential for metastatic colorectal cancer (CRC) treatment, however, resistance remains problematic in <i>KRAS</i>/<i>NRAS</i>/<i>BRAF</i> wild-type patients. RAS protein activator-like 2 (RASAL2) regulates RAS signaling by catalyzing the conversion of RAS. This study investigates the pathogenicity of the germline <i>RASAL2</i> c.2423&#xa0;A &gt; G variant, identified in a high-risk family, and its potential role in CRC progression and therapy resistance. Population analysis reveals its rarity in East Asians (0.01%) but an increased prevalence in Taiwanese CRC patients (1.63%). Functional studies demonstrate that <i>RASAL2</i> c.2423&#xa0;A &gt; G enhances RAS signaling, causing sustained ERK phosphorylation and increased CRC cell proliferation. Additionally, <i>RASAL2</i>-mutant cells require higher doses of cetuximab for ERK suppression and growth inhibition, indicating resistance to anti-EGFR therapy via abnormal RAS activation. According to the American College of Medical Genetics and Genomics criteria, the variant is likely pathogenic. Our study highlights <i>RASAL2</i> c.2423&#xa0;A &gt; G as a potential biomarker for CRC risk and therapy response.</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

The RASAL2 variant promotes aberrant RAS signaling and resistance to anti-EGFR therapy in colorectal cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月23日

查看全文
  • Yu-Min Yeh,
  • Yi-Hsuan Hsu,
  • Yi-Ting Huang,
  • Peng-Chan Lin,
  • Ya-Ting Hsu,
  • Pei-Ying Wu,
  • Meng-Ru Shen

摘要

Anti-EGFR monoclonal antibodies are essential for metastatic colorectal cancer (CRC) treatment, however, resistance remains problematic in KRAS/NRAS/BRAF wild-type patients. RAS protein activator-like 2 (RASAL2) regulates RAS signaling by catalyzing the conversion of RAS. This study investigates the pathogenicity of the germline RASAL2 c.2423 A > G variant, identified in a high-risk family, and its potential role in CRC progression and therapy resistance. Population analysis reveals its rarity in East Asians (0.01%) but an increased prevalence in Taiwanese CRC patients (1.63%). Functional studies demonstrate that RASAL2 c.2423 A > G enhances RAS signaling, causing sustained ERK phosphorylation and increased CRC cell proliferation. Additionally, RASAL2-mutant cells require higher doses of cetuximab for ERK suppression and growth inhibition, indicating resistance to anti-EGFR therapy via abnormal RAS activation. According to the American College of Medical Genetics and Genomics criteria, the variant is likely pathogenic. Our study highlights RASAL2 c.2423 A > G as a potential biomarker for CRC risk and therapy response.