Drug treatment and phenotypic diversity

Therapy resistance

Nature Genetics volume 55, page 1253 (2023)Cite this article

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The emergence of resistance to cancer therapy remains a considerable clinical challenge, but the mechanisms that underpin the evolution of drug-resistant clones are poorly understood. In new work published in Nature, Goyal et al. developed FateMap, a barcode-based framework that enabled them to track the fate of hundreds of thousands of cell clones after drug treatment. Applying the method to vemurafenib-treated melanoma cells highlighted considerable transcriptional diversity in drug-resistant populations derived from a single cell. Importantly, similar observations were recorded in cells from primary tumors from patients treated with targeted therapies. The repertoire of cell fates assumed by resistant cells was a function of both the dose and the type of drug, and diverse transcriptional states were reflected in differences in proliferation, invasion and morphology. Further experiments suggested that the adoption of cell fate after drug treatment was pre-determined, and independent of extrinsic factors such as microenvironmental influences. What governs this phenotypic rewiring remains unknown but these data show that the response to drug treatment depends — at least in part — on the pre-existing variability that exists within clonal populations.

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Safia Danovi

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Correspondence to Safia Danovi.

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Danovi, S. Drug treatment and phenotypic diversity. Nat Genet 55, 1253 (2023). https://doi.org/10.1038/s41588-023-01484-x

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Published: 09 August 2023

Issue Date: August 2023

DOI: https://doi.org/10.1038/s41588-023-01484-x

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