Patient- and Cell Type-Specific Heterogeneity of Metformin Response.

Most FDA approved drugs are not equally effective in all patients, suggesting that identification of biomarkers to predict responders to a chemoprevention agent will be needed to stratify patients and achieve maximum benefit. The goal of this study was to investigate both patient specific and cell-context specific heterogeneity of metformin response, using cancer cell lines fibroblast cell lines and induced pluripotent stem cells differentiated into lung epithelial lineages. We performed transcriptome analysis on both patient-derived fibroblast cell lines and cancer cell lines to assess differential metformin response and identify response genes. We found differences in response to metformin treatment across a variety of cell lines and cellular contexts, suggesting heterogeneity that may be patient and cell-type specific. Gene expression profiling and analysis of metformin sensitive and resistant cells identified differentially expressed genes that may be able to stratify patients into metformin responders and non-responders. Patient derived fibroblast cells, differentiated IPS cells and cancer cells were each treated with their respective IC50 concentrations of metformin and DMSO for 72 hours. Total RNA was extracted, hybridized to the Affymetrix Gene Chip Human Genome U133 Plus 2.0 single arrays and using GeneChip Scanner 3000. Principle Component Analysis (PCA) and unsupervised hierarchical clustering were used to perform quality checks on the samples. Samples from control and treated, and from resistant and sensitive groups were compared using 1-way ANOVA (analysis of variance). Significantly changed genes obtained from ANOVA were prioritized by a combination of P value and fold change.