Integrative approaches for studying the role of noncoding RNAs in influencing drug efficacy and toxicity

ABSTRACT

Introduction

Drug efficacy and toxicity are important factors for evaluation in drug development. Drug metabolizing enzymes and transporters (DMETs) play an essential role in drug efficacy and toxicity. Noncoding RNAs (ncRNAs) have been implicated to influence inter-individual variations in drug efficacy and safety by regulating DMETs. An efficient strategy is urgently needed to identify and functionally characterize ncRNAs that mediate drug efficacy and toxicity through regulating DMETs.

Areas covered

We outline an integrative strategy to identify ncRNAs that modulate DMETs. We include reliable tools and databases for computational prediction of ncRNA targets with regard to their advantages and limitations. Various biochemical, molecular, and cellular assays are discussed for in vitro experimental verification of the regulatory function of ncRNAs. In vivo approaches for association of ncRNAs with drug treatment and toxicity are also reviewed.

Expert opinion

A streamlined integration of computational prediction and wet-lab validation is important to elucidate mechanisms of ncRNAs in the regulation of DMETs related to drug efficacy and safety. Bioinformatic analyses using open-access tools and databases serve as a powerful booster for ncRNA Research in toxicology. Further refinement of computational algorithms and experimental technologies is needed to improve accuracy and efficiency in ncRNA target identification and characterization.

KEYWORDS:

• Drug metabolizing enzymes and transporters
• drug efficacy
• drug toxicity
• gene regulation
• long noncoding RNA
• microRNA
• toxicogenomics

Abbreviations

ADME, absorption-distribution-metabolism and excretion; AGO, Argonaute; CLASH, crosslinking, immunoprecipitation, and sequencing of hybrids; CLIP, crosslinking and immunoprecipitation; DMET, drug metabolizing enzyme and transporter; FREMSA, Fluorescence-based RNA Electrophoretic Mobility Shift Assay; GEO, Gene Expression Omnibus; lncRNA, long noncoding RNA; MFE, minimum free energy; miRNA, microRNA; ncRNA, noncoding RNA; PAR-CLIP, photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation; RISC, RNA-induced silencing complex; shRNA, short hairpin RNA; siRNA, small interference RNA; TCGA, The Cancer Genome Atlas; UTR, untranslated region

Article highlights

• Due to the complexity in regulatory mechanisms of noncoding RNAs, an integrative strategy combining dry-lab and wet-lab approaches can tremendously improve the efficiency in the investigation of ncRNA modulation of genes involved in drug efficacy and toxicity.

• Bioinformatic analysis of ncRNA:target binding characteristics is a powerful and cost-efficient tool for ncRNA target identification before wet-lab validation.

• The use of a combination of wet-lab techniques, such as luciferase reporter assays, functional characterization, and in vivo drug induction, may help overcome the limitations of each assay and allow scientists to obtain conclusive findings.

Declaration of interest

All authors are US Federal Government Employees. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

Reviewer disclosures

A reviewer on this manuscript has disclosed being an employee of Certara and a stock holder of Johnson and Johnson shares. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Disclaimer

The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. Any mention of commercial products is for clarification and is not intended as an endorsement.

Additional information

Funding

This work was funded by FDA/NCTR E0776901.