Abstract
Despite the development of new classes of targeted anti-cancer drugs, the curative treatment of metastatic solid tumors remains out of reach owing to the development of resistance to current chemotherapeutics. Although many mechanisms of drug resistance have been described, there is still a general lack of understanding of the many means by which cancer cells elude otherwise effective chemotherapy. The traditional strategy of isolating resistant clones in vitro, defining their mechanism of resistance, and testing to see whether these mechanisms play a role in clinical drug resistance is time-consuming and in many cases falls short of providing clinically relevant information. In this review, we summarize the use of CRISPR technology, including the promise and pitfalls, to generate libraries of cancer cells carrying sgRNAs that define novel mechanisms of resistance. The existing strategies using CRISPR knockout, activation, and inhibition screens, and combinations of these approaches are described. In addition, specialized approaches to identify more than one gene that may be contributing to resistance, as occurs in synthetic lethality, are described. Although these CRISPR-based approaches to cataloguing drug resistance genes in cancer cells are just beginning to be utilized, appropriately used they promise to accelerate understanding of drug resistance in cancer.
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Acknowledgements
We thank G. Leiman in the Laboratory of Cell Biology for editorial assistance.
Funding
This research was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute.
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Conception and design of the study: GA, HMW and AAB. Drafting the article: GA, HMW, AAB, CCL, MDS, RML, BAM, RWR and MMG. Revision and editing: GA, PM, RWR and MMG. All authors reviewed the final version before submission.
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Alyateem, G., Wade, H.M., Bickert, A.A. et al. Use of CRISPR-based screens to identify mechanisms of chemotherapy resistance. Cancer Gene Ther 30, 1043–1050 (2023). https://doi.org/10.1038/s41417-023-00608-z
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DOI: https://doi.org/10.1038/s41417-023-00608-z
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