Reverse Translational Research of ABCG2 (BCRP) in Human Disease and Drug Response

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Translational research generally takes a bench‐to‐bedside approach, in which laboratory research is translated to address pertinent problems in the clinic. This approach has led to a wealth of new information about human physiology and pathophysiology. However, the approach falters in one key area: the discovery and development of new drug therapies. What is often described as the “valley of death” refers to the large gap between the number of potential drug targets identified through laboratory research each year and the number of new therapies on the market. Notably, budgets of the top 10 pharmaceutical companies totaled $70.5 billion in 2016, with only 22 new drugs being approved by the US Food and Drug Administration (FDA) in the same year.1
So why has translational research failed to result in more approved prescription drugs? The leading cause for failure of drugs in phase II and III clinical trials is lack of efficacy, followed by lack of safety and market need.3 Lack of efficacy can be attributed to the failure of methods used in drug development to reliably predict therapeutic drug response. For example, cell‐based research fails to fully recapitulate the complexity of the human body as a whole system, whereas large differences in pharmacologic action between humans and preclinical animal species may result in false predictions of drug response. Further, differences in drug metabolism and transport among species may result in poor predictions of pharmacokinetics, which in turn may lead to lack of efficacy or safety in clinical trials. Because of these species differences, drug developers are increasingly relying on human genetic data as well as in vitro assays from human cells. In vitro drug metabolism studies are typically performed in primary or cryopreserved hepatocyte cultures and microsomes derived from human liver. However, hepatocytes lose much of their canalicular drug transporters during culture and undergo substantial dedifferentiation when plated.4 The artificial environment of the system also has no flow or shear stress, which has been shown to affect transporter expression in mice.6
Increasingly, a vast amount of human data has been extracted and stored in publicly accessible databases, providing an enabling resource for reverse translation. Reverse translational research offers a complementary approach to traditional translational research. In particular, in reverse translation, the challenge for the researcher is to explain the observational data through detailed and in‐depth mechanistic studies, reproducing clinical findings in preclinical in vitro or in vivo models that can then be used for further translational research. This kind of research is especially powerful in the context of drug development, as it not only improves the safety and efficacy of newly developed drugs but also identifies potential new targets or clinical subtypes of disease that can inform future drug development. With the increasing availability of computational tools and decreasing costs of high‐throughput genetic screens, reverse translational research has become a mainstay of human genetic studies, and is becoming an important tool in discovering the endogenous role of proteins as well.
Against this backdrop reverse translational research in the area of membrane transporters has advanced rapidly. Traditionally, membrane transporters have been of particular interest to drug developers because of their multiple roles in drug toxicity and pharmacokinetics. However, more recently, transporters have increasingly been recognized as enticing drug targets, as human genetic studies have revealed their roles in the pathophysiology of both rare and common disease.7 For example, genome‐wide association studies focused on serum uric acid levels have revealed an essential role for URAT1 (SLC22A12) in hyperuricemia, and supported the development of a new drug targeted to the transporter (lesinurad) in the treatment of gout.
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