Abstract
Cancer evolution can engender tumours with the ability to resist multiple treatments with distinct chemical structures and mechanisms of action, and this multidrug resistance (MDR) phenotype has long been a substantial challenge in cancer therapy. Despite the established benefits of systemic treatments including chemotherapies, molecularly targeted therapies and immunotherapies across various cancers, MDR inevitably occurs at some point during the course of the disease and its treatment in most patients. Since the discovery of MDR in the 1960s, our understanding of the underlying mechanisms has deepened. However, few strategies are currently available to combat MDR in the clinical setting, and approaches to systematically translate knowledge of new MDR mechanisms and treatments from the laboratory into the clinic are lacking. In this Review, we focus on preclinical and clinical advances in understanding MDR, with an emphasis on resistance to chemotherapy and targeted therapy. We also summarize progress made in translating these findings from bench to bedside through the development of potential strategies to overcome MDR and thus improve patient outcomes.
Key points
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Multidrug resistance (MDR) is driven first and foremost by ATP-binding cassette efflux pumps and is further reinforced by tumour heterogeneity, epigenetic changes, signalling pathway interactions and the tumour microenvironment.
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Many drug resistance mechanisms, despite clear evidence that they confer cross-resistance to multiple agents, are often discussed only in general terms of ‘drug resistance’; emphasizing contributions of these mechanisms to MDR is important to the clinical translation of MDR-reversal strategies.
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Robust preclinical models are vital to bridge the gap between basic research and clinical application. Traditional xenograft models often fail to reflect the complexities of cancer in patients; genetically engineered mouse models and patient-derived xenograft models are typically more representative but still do not fully recapitulate tumour heterogeneity and immune interactions, necessitating further refinement.
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Addressing MDR will require combinations of molecularly targeted agents and other therapies, immune modulation and innovative drug delivery methods to target multiple resistance pathways simultaneously.
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Incorporating molecular profiling and biomarker-based diagnostics will facilitate progress in MDR research by connecting preclinical findings with clinical outcomes.
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Acknowledgements
X.Y.C. expresses thanks for the teaching fellowship from the Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University. The work of M.G. is supported by the National Natural Science Foundation of China (grant no. 82173855) and the Zhejiang Provincial Science and Technology Program (grant no. 2022R51002).
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M.G, X.-Y.C., P.H. J.S.F. and Z.-F.K. researched data for the article. M.G, X.-Y.C., D.-H.Y, Z.-F.K. and Z.-S.C. contributed substantially to discussion of the content. M.G, X.-Y.C., P.H. and Z.-X.W wrote the article. M.G, X.-Y.C., J.S.F., D.-H.Y, Z.-X.W, Z.-F.K. and Z.-S.C reviewed and/or edited the manuscript before submission.
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Ge, M., Chen, XY., Huang, P. et al. Understanding and overcoming multidrug resistance in cancer. Nat Rev Clin Oncol 22, 760–780 (2025). https://doi.org/10.1038/s41571-025-01059-1
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DOI: https://doi.org/10.1038/s41571-025-01059-1
