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

  • Nat Commun. 2026 Apr 17;17(1):5369. doi: 10.1038/s41467-026-72062-y.
Min Li  #  1  2 ,  Ying Xue  #  3 ,  Yuhan Chang  #  1  2 ,  Fan Xu  #  1  2 ,  Feizhen Wu  4 ,  Xinjian Tian  5 ,  Jie Hu  6 ,  Yijun Song  6 ,  Xufen Yu  5 ,  Fei Zhou  7 ,  Caicun Zhou  8 ,  Xin Cao  9 ,  Mei Wang  10 ,  Qihong Huang  11  12
Affiliations
  • 1. Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2. Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3. Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
  • 4. Intelligent Medicine Institute, Fudan University, Shanghai, China.
  • 5. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China.
  • 6. Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 7. Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 8. Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
  • 9. Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 10. Department of Geriatrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 11. Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 12. Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41997974 DOI: 10.1038/s41467-026-72062-y
Abstract

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.

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