Pharmacokinomic Profiling Using Patient-Derived Cell Lines Predicts Sensitivity to Imatinib in Dermatofibrosarcoma...

Dermatofibrosarcoma protuberans (DFSP) is a rare sarcoma, characterized by a COL1A1-PDGFB fusion. Imatinib, a multi-target tyrosine kinase inhibitor, is a standard treatment of DFSP. However, resistance emerges in 10-50% of cases. There is an urgent need for predictive biomarkers to refine the patient selection and improve therapeutic outcomes. We aimed to identify predictive biomarkers for imatinib response and explored a pharmacokinomic approach using in vitro assays with patient-derived DFSP cell lines. Four DFSP cell lines that we established were analyzed for tyrosine kinase activities on PamChip, a three-dimensional peptide array, in the presence and absence of imatinib, along with an imatinib-sensitive cell line, GIST-T1, as a positive control. Drug screening was also performed using 60 FDA-approved tyrosine kinase inhibitors, including imatinib. The kinomic profiles were compared with the kinase inhibitor screening results to identify predictive druggable targets. Drug sensitivity was associated with increased activity of PDGFRB, as indicated by the PamChip assay and Western blotting. Furthermore, imatinib sensitivity correlated with the activity of three kinases: FER, ITK, and VEGFR1, suggesting their potential as potential predictive biomarkers. Our cell-based pharmacokinomic approach using patient-derived DFSP cell lines would facilitate the identification of resistant cases to imatinib and guide alternative therapeutic strategies.