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Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters
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Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters
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Journal Article
Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters
2023
Overview
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.This Review summarizes how the structural details that were revealed by cryo-electron microscopy and X-ray crystallography and insights into molecular basis of polyspecificity and mechanistic studies shaped the understanding of the role of ATP-binding cassette transporter in cancer multidrug resistance, culminating in new therapeutic approaches to sensitize multidrug-resistant cancer cells to conventional and targeted therapies.
