LAUSR

P-glycoprotein, ABCG2, and MRP1 are members of the ATP-binding cassette (ABC) transporter superfamily that utilize energy from ATP-binding and hydrolysis to efflux a broad range of chemically dissimilar substrates including anticancer drugs. As a consequence, they play an important role in the pharmacokinetics and bioavailability of many drugs; in particular, their role in multidrug resistance in cancer cells as well as at the blood–brain barrier has been the subject of studies for decades. However, the atomic structures of these transporters in the presence of substrates or modulators and at different stages of the ATP-hydrolysis cycle have only recently been resolved by using cryo-electron microscopy. In addition, new animal models have shed new light on our understanding of the role of these transporters at the blood–brain barrier. This new information should open doors for the design of novel chemotherapeutics and treatments to bypass recognition by ABC drug pumps to overcome clinical drug resistance. In this review, we discuss the most recent advances in our understanding of ligand interactions and mechanistic aspects of drug transport based on atomic structures of these transporters as well as the development of new in vivo models to study their role in clinical drug resistance in cancer.