Cancer Management and Research (Nov 2018)
Identification of mTOR inhibitor-resistant genes in cutaneous squamous cell carcinoma
Abstract
Seong-Lan Yu,1 Dong Chul Lee,2 Seung Woo Baek,3 Do Yeun Cho,3 Jong Gwon Choi,3 JaeKu Kang1 1Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Republic of Korea; 2Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea; 3Department of Oncology-Hematology, Konyang University Hospital, Daejeon, Republic of Korea Purpose: The PI3K/AKT/mTOR pathway is frequently activated in various squamous cell carcinomas (SCCs). Although mTOR inhibitors are suggested as effective treatments in immunosuppressed patients with metastatic SCC, they are still not proven to be favorable in treating skin SCC patients not undergoing immunosuppressive therapy. Moreover, the exact mechanism of the mTOR signaling pathway in SCC has not yet been identified. In this study, we aimed to determine the genes associated with mTOR inhibitors in skin SCC.Materials and methods: The identification of cell viability according to concentration of everolimus and Western blot was done. To analyze the global gene expression profiles, A431 and HSC-1 cells were treated with dimethyl sulfoxide (DMSO) or 100 nM of everolimus for 72 hours. Furthermore, differentially expressed genes (DEGs) were identified using Affymetrix analysis. To identify the gene network associated with everolimus resistance in SCC cells, pathway analysis was performed using the Ingenuity Pathway Analysis (IPA) tool.Results: The effects of cell death with respect to the mTOR inhibitor concentration were observed in the HSC-1 cell line; however, the mTOR inhibitor did not show effective cytotoxic activity in the A431 cell line. p-mTOR concentration also diminished with respect to everolimus concentrations in the HSC-1 cell line. Moreover, the microarray results showed that the MYC/CCND1/TP73/NUPR1/SBD/ERBB2/CDKN2B genes were related to mTOR inhibitor resistance. However, CCND1 gene overexpression was most closely related to mTOR inhibitor resistance.Conclusion: We identified mTOR inhibitor resistance genes, and our findings may help select therapeutic targets in skin SCC. Keywords: mTOR inhibitor, squamous cell carcinoma, gene profiling, CCND1 gene
