Multi-omic profiling and real time ex vivo modelling of imatinib-resistant dermatofibrosarcoma protuberans with fibrosarcomatous transformation

• Published in: Human cell : official journal of Human Cell Research Society Vol. 36; no. 6; pp. 2228 - 2236
• Main Authors: Chan, Jason Yongsheng, Lee, Elizabeth Chun Yong, Li, Zhimei, Lee, Jing Yi, Lim, Abner Herbert, Poon, Eileen
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.11.2023; Springer Nature B.V
• Subjects: Angiogenesis; Antiangiogenic agents; Biomedical and Life Sciences; CD34 antigen; Cell Biology; Cell Line; Chromosome 9; Chromosome deletion; Collagen (type I); Dermatofibrosarcoma protuberans; Epidermal growth factor receptors; Gefitinib; Gene deletion; Gene set enrichment analysis; Genetic transformation; Genomes; Gynecology; Imatinib; Immunohistochemistry; Kinases; Life Sciences; Metastases; Oncology; Platelet-derived growth factor; Protein-tyrosine kinase; Reproductive Medicine; Sarcoma; Signal transduction; Sox10 protein; Stem Cells; Surgery; Tumors; Whole genome sequencing; Rare cancers; AYA cancer; Precision oncology; Multi-omics; Patient-derived xenograft
• ISSN: 1749-0774; 0914-7470; 1749-0774
• DOI: 10.1007/s13577-023-00974-8

Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma, with the risk of aggressive fibro-sarcomatous transformation. Limited effective options are available for un-resectable or metastatic DFSP beyond targeting the oncogenic PDGF pathway with imatinib therapy. We established a patient-derived xenograft (PDX) and cell line model (designated MDFSP-S1) of imatinib-resistant DFSP with fibro-sarcomatous transformation. Whole genome sequencing identified high-level amplification at chromosomes 17 and 22, whilst 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 tumour, PDX and cell line model. Immunohistochemistry profiles of the PDX model were consistent with the patient’s tumour sample (CD34 + /MIB1 + /SOX10− ). Gene set enrichment analysis highlighted top-scoring Hallmark gene sets in several oncogenic signalling pathways, including potentially targetable MTORC1 signalling 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 and 10 µM at 72 h. No significant activity was observed with imatinib, palbociclib, everolimus, olaparib, gefitinib and erlotinib (IC50 all > 10 µM). In conclusion, we established MDFSP-S1, a new PDX and cell line model of imatinib-resistant DFSP with fibro-sarcomatous transformation.