Student The University of Tokyo bunkyo-ku, Tokyo, Japan
Background The effective treatments for canine histiocytic sarcoma (CHS) remain to be established. We previously revealed that the sensitivities to three molecular-targeted drugs, Dasatinib, Trametinib, and Ponatinib, were significantly different among CHS cell lines.
Hypothesis/Objectives To investigate the gene expression profiles associated with the sensitivity to the three molecular-targeted drugs in CHS cell lines.
Methods RNA was extracted from twelve CHS cell lines, and the gene expression profiles were analyzed by RNA sequencing. Differentially expressed genes (DEGs) were extracted by the comparisons between the drug-sensitive and -resistant cell lines, and they were subjected to KEGG pathway analysis. The differences in the expression levels of these DEGs were validated by RT-qPCR.
Results The clustering analysis showed that CHS cell lines were divided into two distinct clusters, and one cluster consisted of the three most drug-resistant cell lines (Figure 1). The comparisons of these three cell lines and the three most drug-sensitive cell lines extracted 624 DEGs, and KEGG pathway analysis indicated these DEGs were enriched with those related to the regulation of PI3K-Akt pathway. RT-qPCR analysis confirmed the significant upregulations of TLR4, IL6R, PKN1, PPP2R3C, and SPP1 genes and the significant downregulations of F2R, GNG12, COL4A2, PDGFA, ITGA3, and LAMA3 genes in the three drug-resistant cell lines compared to other nine cell lines. Conclusions and clinical importance The results of this study suggested that the differences in the activations status of intracellular signaling pathways including PI3K-Akt pathways were associated with the differences in the sensitivities to the three molecular-targeted drugs.
