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- Title
High-throughput screening and genome-wide analyses of 44 anticancer drugs in the 1000 Genomes cell lines reveals an association of the NQO1 gene with the response of multiple anticancer drugs.
- Authors
Akhtari, Farida S.; Green, Adrian J.; Small, George W.; Havener, Tammy M.; House, John S.; Roell, Kyle R.; Reif, David M.; McLeod, Howard L.; Wiltshire, Timothy; Motsinger-Reif, Alison A.
- Abstract
Cancer patients exhibit a broad range of inter-individual variability in response and toxicity to widely used anticancer drugs, and genetic variation is a major contributor to this variability. To identify new genes that influence the response of 44 FDA-approved anticancer drug treatments widely used to treat various types of cancer, we conducted high-throughput screening and genome-wide association mapping using 680 lymphoblastoid cell lines from the 1000 Genomes Project. The drug treatments considered in this study represent nine drug classes widely used in the treatment of cancer in addition to the paclitaxel + epirubicin combination therapy commonly used for breast cancer patients. Our genome-wide association study (GWAS) found several significant and suggestive associations. We prioritized consistent associations for functional follow-up using gene-expression analyses. The NAD(P)H quinone dehydrogenase 1 (NQO1) gene was found to be associated with the dose-response of arsenic trioxide, erlotinib, trametinib, and a combination treatment of paclitaxel + epirubicin. NQO1 has previously been shown as a biomarker of epirubicin response, but our results reveal novel associations with these additional treatments. Baseline gene expression of NQO1 was positively correlated with response for 43 of the 44 treatments surveyed. By interrogating the functional mechanisms of this association, the results demonstrate differences in both baseline and drug-exposed induction. Author summary: In the burgeoning field of personalized medicine, genetic variation is recognized as a major contributor to patients' differential responses to drugs. Lymphoblastoid cell lines (LCLs) are a consistent and convenient representation of cells used for in vitro research. Human genome sequencing with LCLs can identify new genes that influence individuals' drug responses, including the dose-response relationship, which describes the relationship between physiological response and the amount of exposure to a substance. In this work, we conduct high-throughput screening and genome-wide association mapping using 680 LCLs from the 1000 Genomes Project to identify new genes that influence individual response to 44 widely used anticancer drugs. We found the NQO1 gene to be associated with the dose-response of several drugs, namely arsenic trioxide, erlotinib, trametinib, and the paclitaxel + epirubicin combination, and performed follow-up analyses to better understand its functional role in drug response. Our results indicate NQO1 expression is correlated with increased drug resistance and provide some evidence that SNP rs1800566 influences drug response by altering protein activity for these four treatments. With further research, NQO1 has potential use as a therapeutic target, for example, suppressing NQO1 expression to increase sensitivity to particular drugs.
- Subjects
UNITED States. Food &; Drug Administration; HIGH throughput screening (Drug development); ANTINEOPLASTIC agents; GENETIC variation; LYMPHOBLASTOID cell lines; GENOME-wide association studies; PHARMACOGENOMICS; DRUG resistance
- Publication
PLoS Genetics, 2021, Vol 17, Issue 8, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1009732