Cancer cells frequently display intrinsic or acquired resistance to chemically diverse anticancer drugs, limiting therapeutic success. Among the main mechanisms of this multidrug resistance is the overexpression of ATP-binding cassette (ABC) transporters that mediate drug efflux, and, specifically, ABCB1, ABCG2 and ABCC1 are known to cause cancer chemoresistance. High-resolution structures, biophysical and in silico studies have led to tremendous progress in understanding the mechanism of drug transport by these ABC transporters, and several promising therapies, including irradiation-based immune and thermal therapies, and nanomedicine have been used to overcome ABC transporter-mediated cancer chemoresistance. In this Review, we highlight the progress achieved in the past 5 years on the three transporters, ABCB1, ABCG2 and ABCC1, that are known to be of clinical importance. We address the molecular basis of their broad substrate specificity gleaned from structural information and discuss novel approaches to block the function of ABC transporters. Furthermore, genetic modification of ABC transporters by CRISPR–Cas9 and approaches to re-engineer amino acid sequences to change the direction of transport from efflux to import are briefly discussed. We suggest that current information regarding the structure, mechanism and regulation of ABC transporters should be used in clinical trials to improve the efficiency of chemotherapeutics for patients with cancer.
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The authors thank G. Leiman for editorial help. This work is funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.
The authors declare no competing interests.
Peer review information
Nature Reviews Cancer thanks Stephen Aller, who co-reviewed with Christina Le, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Gene expression atlas: https://www.ebi.ac.uk/gxa/home
Human Protein Atlas for pathology: https://www.proteinatlas.org/humanproteome/pathology
RCSB Protein Data Bank (PDB): https://www.rcsb.org/
- ABC transporters
ATP-binding cassette proteins, a superfamily of transporters that transport nutrients, ions, lipids or drugs across the cell membrane using energy derived from ATP hydrolysis.
- Blood–brain barrier
A barrier made of endothelial cells that selectively blocks passage of unwanted toxins, including anticancer drugs, and bacteria from the bloodstream to the brain.
- Collateral sensitivity
Increased sensitivity of drug-resistant cancer cells owing to the presence of resistance markers including ABC transporters.
- DNA-capped quantum dots
DNA-capped quantum dots are prepared by attaching strands of DNA to inorganic nanocrystals, and such quantum dots are used for imaging cellular processes in vitro and in vivo in animal studies.
- Drug transport
Transport of drugs across the eukaryotic cell membrane, either by facilitated diffusion (small hydrophobic drugs) or by uptake or efflux pumps, which require ion gradients or ATP as the energy source for active transport.
- Half transporter
An ABC transporter having one transmembrane domain containing six to eight helices and one nucleotide-binding domain. The functional unit is either a homodimer or heterodimer.
- Molecular dynamics (MD) simulations
MD simulations are a computer-based method for analysing the movement of residues within a protein, interaction of ligands with a protein or conformational changes owing to mutations.
- Multidrug-resistant cancer
Cancer cells become unresponsive to not only the anticancer drug administered but also various other drugs.
It is the precise arrangement of atoms or functional groups in a small molecule required for specific interactions with its biological target such as a receptor, transporter or an enzyme for its optimal activity.
Certain ABC transporters, particularly ABCB1, ABCG2 or ABCC1, can transport various chemically dissimilar amphipathic and hydrophobic compounds, including drugs.
- Repurposed drugs
Identification of new uses or targets for approved drugs that are not within the original medical indication.
- RNA interference
Use of single-stranded or double-stranded RNA, including siRNA, shRNA or miRNA to block the translation of a target gene of interest by binding its mRNA, causing its degradation.
- Small-molecule inhibitors
Low-molecular-weight drugs or chemicals that can inhibit a target protein and are usually easy to synthesize and can readily enter cells.
- Structure–activity relationship
(SAR). It is a method used to determine the correlation between chemical structure and biological activity of compounds, including drugs.
- Walker motifs
The Walker A and Walker B motifs with highly conserved 3D structures are present in ATP-binding and GTP-binding proteins, including F-type, P-type, V-type ATPases and ABC transporters.
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Sajid, A., Rahman, H. & Ambudkar, S.V. Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters. Nat Rev Cancer 23, 762–779 (2023). https://doi.org/10.1038/s41568-023-00612-3