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Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters

Nature Reviews Cancer volume 23, pages 762–779 (2023)Cite this article

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Abstract

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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Fig. 1: Selected substrates transported by ABCB1, ABCG2 and ABCC1.
Fig. 2: Structures of three ATP-binding cassette transporters.
Fig. 3: Substrate-binding pockets of ATP-binding cassette transporters and the drug transport cycle.
Fig. 4: Emerging therapies targeting ATP-binding cassette transporters.

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Acknowledgements

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.

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Authors and Affiliations

  1. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Andaleeb Sajid, Hadiar Rahman & Suresh V. Ambudkar

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  1. Andaleeb Sajid
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  2. Hadiar Rahman
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  3. Suresh V. Ambudkar
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The authors contributed equally to all aspects of the article.

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Correspondence to Suresh V. Ambudkar.

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Related links

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/

Glossary

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.

Pharmacophore

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.

Polyspecificity

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

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