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<p>Epithelial-mesenchymal transition drives tumor metastasis and therapeutic resistance, yet few treatments have been developed that target this process. Here, we show that <i>ELMO2</i> represents a specific vulnerability in mesenchymal-like cells. <i>ELMO2</i> suppression induces excessive autophagy and cell death via FAK activity inhibition. We identify ELMO3 as a functional paralog that compensates for ELMO2 loss, establishing a synthetic lethal interaction. The epithelial-mesenchymal transition core regulator ZEB1 represses <i>ELMO3</i> transcription in mesenchymal-like cells, rendering them sensitive to ELMO2 blockade. <i>ELMO3</i> is significantly downregulated in epithelial-mesenchymal transition-associated EGFR inhibitor-resistant cells. Furthermore, the survival of these resistant, mesenchymal-like cells depends on ELMO2/FAK signaling. Through structure-based screening, we identify C52, a small-molecule ELMO2 inhibitor that effectively kills <i>ELMO3</i>-low lung cancer cells and EGFR inhibitor-resistant cells. Our study uncovers an ELMO2-ELMO3 synthetic lethal interaction and establishes <i>ELMO2</i> as a potential therapeutic target for mesenchymal-like cancer and drug-resistant non-small cell lung cancer.</p>

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ELMO2 is a therapeutic vulnerability in mesenchymal-like and drug-resistant non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月17日

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  • Min Li,
  • Ying Xue,
  • Yuhan Chang,
  • Fan Xu,
  • Feizhen Wu,
  • Xinjian Tian,
  • Jie Hu,
  • Yijun Song,
  • Xufen Yu,
  • Fei Zhou,
  • Caicun Zhou,
  • Xin Cao,
  • Mei Wang,
  • Qihong Huang

摘要

Epithelial-mesenchymal transition drives tumor metastasis and therapeutic resistance, yet few treatments have been developed that target this process. Here, we show that ELMO2 represents a specific vulnerability in mesenchymal-like cells. ELMO2 suppression induces excessive autophagy and cell death via FAK activity inhibition. We identify ELMO3 as a functional paralog that compensates for ELMO2 loss, establishing a synthetic lethal interaction. The epithelial-mesenchymal transition core regulator ZEB1 represses ELMO3 transcription in mesenchymal-like cells, rendering them sensitive to ELMO2 blockade. ELMO3 is significantly downregulated in epithelial-mesenchymal transition-associated EGFR inhibitor-resistant cells. Furthermore, the survival of these resistant, mesenchymal-like cells depends on ELMO2/FAK signaling. Through structure-based screening, we identify C52, a small-molecule ELMO2 inhibitor that effectively kills ELMO3-low lung cancer cells and EGFR inhibitor-resistant cells. Our study uncovers an ELMO2-ELMO3 synthetic lethal interaction and establishes ELMO2 as a potential therapeutic target for mesenchymal-like cancer and drug-resistant non-small cell lung cancer.