The mammalian target of rapamycin (mTOR) inhibitors, a set of promising potential anti-cancer agents, has shown response variability among individuals. This study aimed to identify novel biomarkers and mechanisms that might influence the response to Rapamycin and Everolimus. Genome-wide association (GWA) analyses involving single nucleotide polymorphisms (SNPs), mRNA, and microRNAs microarray data were assessed for association with area under the cytotoxicity dose response curve (AUC) of two mTOR inhibitors in 272 human lymphoblastoid cell lines (LCLs). Integrated analysis among SNPs, expression data, microRNA data and AUC values were also performed to help select candidate genes for further functional characterization. Functional validation of candidate genes using siRNA screening in multiple cell lines followed by MTS assays for the two mTOR inhibitors were performed. We found that 16 expression probe sets (genes) that overlapped between the two drugs were associated with AUC values of two mTOR inhibitors. One hundred and twenty seven and one hundred SNPs had P < 10(-4), while 8 and 10 SNPs had P < 10(-5) with Rapamycin and Everolimus AUC, respectively. Functional studies indicated that 13 genes significantly altered cell sensitivity to either one or both drugs in at least one cell line. Additionally, one microRNA, miR-10a, was significantly associated with AUC values for both drugs and was shown to repress expression of genes that were associated with AUC and desensitize cells to both drugs. In summary, this study identified genes and a microRNA that might contribute to response to mTOR inhibitors.
Keywords: Everolimus; Rapamycin; genome-wide association; mTOR; pharmacogenomics.