Background Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma, with the risk of aggressive fibrosarcomatous transformation. Limited effective options are available for unresectable or metastatic DFSP beyond targeting the oncogenic PDGF pathway with imatinib therapy. Methods We established a patient-derived xenograft (PDX) and cell-line model (designated MDFSP-S1) of imatinib-resistant DFSP with fibrosarcomatous transformation. Results Whole genome sequencing identified high level amplification at chromosomes 17 and 22, while homozygous deep deletion was demonstrated at chromosome 9 (CDKN2A, CDKN2B, MTAP). RNA sequencing followed by Sanger sequencing confirmed the pathognomonic COL1A1-PDGFB t(17;22) rearrangement in the original tumor, PDX and cell-line model. Immunohistochemistry profile of the PDX model was consistent with the patient’s tumor sample (CD34+/MIB1+/SOX10-). Gene set enrichment analysis highlighted top-scoring Hallmark gene sets in several oncogenic signaling pathways, including potentially targetable MTORC1 signaling and angiogenesis pathways. Antiangiogenic agents (sunitinib, regorafenib, pazopanib, axitinib) and the third-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib exhibited modest anti-proliferative activity in the cell-line, with IC50 values between 1 μM and 10 μM at 72 hours. No significant activity was observed with imatinib, palbociclib, everolimus, olaparib, gefitinib and erlotinib (IC50 all > 10 μM). Conclusions In conclusion, we established MDFSP-S1, a new PDX and cell line model of imatinib-resistant DFSP with fibrosarcomatous transformation.