3-Dimensional micropillar drug screening identifies FGFR2-IIIC overexpression as a potential target in metastatic giant cell tumor

Abstract

We established two patient derived tumor cells (PDCs) from right and left pulmonary metastatic lesions respectively of a patient with giant cell tumor. At that time, patient-derived tumor cells from right and left surgical specimens were collected and cultured. High-throughput screening (HTS) for 24 drugs was conducted with a micropillar/microwell chip platform using giant cell tumor PDCs. Using 6 doses per drug in 6 replicates for giant cell tumor PDCs, the dose response curves and corresponding IC50 values were calculated from the scanned images using the S+ Chip Analyzer. A sensitive response was more significantly achieved for AZD4547 (FGFR2 inhibitor) in giant cell tumor PDCs originated from the right pulmonary nodule under the micropillar/microwell chip platform using 3D culture. This sensitivity was consistent with the target expression patterns of giant cell tumor PDCs (FGFR2-IIIC mRNA expression in giant cell tumor PDCs originated from the right pulmonary nodule was increased significantly as compared to those originated from left). However, in a conventional 2D cultured MTT assay, there was no difference for IC50 values of AZD4547 between giant cell tumor PDCs originated from right and left pulmonary nodules. An HTS platform based on 3D culture on micropillar/microwell chips and PDC models could be applied as a useful preclinical tool to evaluate the intrapatient tumor/response heterogeneity. This platform based on 3D culture might reflect far better the relation between the tumor-biology and the matched targeted agent as compared to a conventional 2D cultured MTT assay.