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.