2. Academic Validation
  3. Discoidin domain receptor inhibitor DDR1-IN-1 induces autophagy and necroptotic cell death in malignant peripheral nerve sheath tumor

Discoidin domain receptor inhibitor DDR1-IN-1 induces autophagy and necroptotic cell death in malignant peripheral nerve sheath tumor

  • Cell Death Discov. 2025 Mar 1;11(1):83. doi: 10.1038/s41420-025-02367-2.
Guan-Yi Lai 1,  Yu-Cheng Lee 1,  Hao-Jui Weng 2 3 4 5,  Kuei-Hung Lai 6 7 8,  Min-Chen Hsiang 1,  Kai-Yu Hsu 1,  Chung-Ping Liao 9 10 11 12
Affiliations

Affiliations

  • 1 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
  • 2 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
  • 3 Department of Dermatology, Taipei Medical University-Shuang Ho Hospital, New Taipei City, 23561, Taiwan.
  • 4 Department of Dermatology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
  • 5 International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
  • 6 Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan.
  • 7 PhD Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan.
  • 8 Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan.
  • 9 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. chungpingliao@tmu.edu.tw.
  • 10 International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. chungpingliao@tmu.edu.tw.
  • 11 Cancer Research Center, Taipei Medical University Hospital, Taipei, 11031, Taiwan. chungpingliao@tmu.edu.tw.
  • 12 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, 11696, Taiwan. chungpingliao@tmu.edu.tw.
PMID: 40025071 DOI: 10.1038/s41420-025-02367-2
Abstract

Malignant peripheral nerve sheath tumor (MPNST) is a soft tissue sarcoma commonly associated with the tumor-predisposition disorder neurofibromatosis 1. The extracellular matrix collagens contribute to many fibrotic tumors; however, the role of collagen signaling in MPNST was unclear. This study investigated the effects of blocking the interaction between collagens and their receptors in MPNST. We first analyzed the expressions of collagen family proteins in MPNSTs and found an overall increase compared to neurofibroma. Treatment of DDR1-IN-1, a small molecule inhibitor for the collagen receptor Discoidin Domain Receptor, induced a robust MPNST cell death, highlighting the dependence of MPNST survival on collagen signaling. DDR1-IN-1 induced MPNST cell death by activating Autophagy and Necroptosis signaling. Treatment of Necroptosis inhibitors necrostatin-1 or necrosulfonamide reduced the numbers of DDR1-IN-1-induced necrotic cells and autolysosomes, suggesting that the autophagic process depends on Necroptosis activation. Combinations of DDR1-IN-1 with Other anti-MPNST agents revealed synergistic activities against MPNST. In summary, this study discovered a critical MPNST death signaling induced by the small molecule DDR1-IN-1, which might shed light on future MPNST therapeutic strategies.

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