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Updated: May 8, 2026
A Semi-Quantitative Drug Affinity Responsive Target Stability (DARTS) assay for studying Rapamycin/mTOR interaction
Published on: August 27, 2019
Genome-wide association study for biomarker identification of Rapamycin and Everolimus using a lymphoblastoid cell
Jing Jiang1, Brooke L Fridley, Qiping Feng
1Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, MN, USA.
Abstract:
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.
Insights
This study identified genes and a microRNA (miR-10a) influencing responses to mammalian target of rapamycin (mTOR) inhibitors like Rapamycin and Everolimus, offering potential biomarkers for cancer therapy. These findings could personalize anti-cancer drug efficacy.
Area of Science:
- Genomics and Molecular Biology
- Pharmacogenomics
- Cancer Therapeutics
Background:
- Mammalian target of rapamycin (mTOR) inhibitors show variable efficacy in cancer treatment.
- Identifying biomarkers for mTOR inhibitor response is crucial for personalized medicine.
Purpose of the Study:
- To discover novel biomarkers and mechanisms affecting individual responses to Rapamycin and Everolimus.
- To investigate the association of genetic variations (SNPs), gene expression (mRNA), and microRNAs with mTOR inhibitor cytotoxicity.
Main Methods:
- Genome-wide association (GWA) analyses were performed on 272 lymphoblastoid cell lines (LCLs).
- Microarray data for SNPs, mRNA, and microRNAs were analyzed for association with drug response (AUC).
- Functional validation using siRNA screening and MTS assays identified key genes and microRNAs.
Main Results:
- 16 overlapping genes were associated with the cytotoxicity of both mTOR inhibitors.
- Significant associations were found between SNPs and drug response (AUC) for Rapamycin and Everolimus.
- 13 genes altered cell sensitivity, and miR-10a was linked to drug response, repressing AUC-associated genes and desensitizing cells.
Conclusions:
- Genes and miR-10a are potential contributors to variable responses to mTOR inhibitors.
- This research provides a foundation for developing predictive biomarkers in cancer treatment.
- Understanding these mechanisms can guide the development of more effective mTOR inhibitor-based therapies.
