Studying clonal dynamics in response to cancer therapy using high-complexity barcoding
Abstract
Resistance to cancer therapies presents a significant clinical challenge. Recent studies have revealed intratumoral heterogeneity as a source of therapeutic resistance. However, it is unclear whether resistance is driven predominantly by pre-existing or de novo alterations, in part because of the resolution limits of next-generation sequencing. To address this, we developed a high-complexity barcode library, ClonTracer, which enables the high-resolution tracking of more than 1 million cancer cells under drug treatment. In two clinically relevant models, ClonTracer studies showed that the majority of resistant clones were part of small, pre-existing subpopulations that selectively escaped under therapeutic challenge. Moreover, the ClonTracer approach enabled quantitative assessment of the ability of combination treatments to suppress resistant clones. These findings suggest that resistant clones are present before treatment, which would make up-front therapeutic combinations that target non-overlapping resistance a preferred approach. Thus, ClonTracer barcoding may be a valuable tool for optimizing therapeutic regimens with the goal of curative combination therapies for cancer.
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Short-term targeted inhibitor treatment can lead to a small subset of drug-insensitive cells in both patient tumors and laboratory models within 1-14 days.
“Short-term targeted inhibitor treatment can lead to a small subset of drug-insensitive cells in both patient tumors and laboratory models within 1–14 days, a timeframe less likely to induce permanent genetic alterations [114,115,116].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [114]
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- Authors
- Bhang, H.-E. C., Ruddy, D. A., Krishnamurthy Radhakrishna, V., Caushi, J. X., Zhao, R., Hims, M. M., Singh, A. P., Kao, I., Rakiec, D., Shaw, P., Balak, M., Raza, A., Ackley, E., Keen, N., Schlabach, M. R., Palmer, M., Leary, R. J., Chiang, D. Y., Sellers, W. R., Michor, F., Cooke, V. G., Korn, J. M., & Stegmeier, F.
- Affiliations
- Harvard University (US)
- Corresponding author
- Stegmeier, Frank
- ORCID
- Venue
- Nature Medicine
- Published
- 2015-04-13
- Volume
- 21
- Issue
- 5
- Pages
- 440-448
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1987191607
- Cited by
- 507
- References
- 19
- Citations by year
- 2026: 31 · 2025: 29 · 2024: 45 · 2023: 58 · 2022: 41 · 2021: 54 · 2020: 44 · 2019: 52 · 2018: 45 · 2017: 43 · 2016: 49 · 2015: 16
- FWCI
- 16.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (U54CA143798)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- clonal dynamics, cancer therapy resistance, intratumoral heterogeneity, resistant clones, combination therapy, single-cell tracking
- MeSH terms
- Erlotinib Hydrochloride, Crizotinib, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Cell Differentiation, DNA, Humans, Lung Neoplasms, Models, Theoretical, Neoplasms, Oligonucleotides, Pyrazoles, Pyridines, Quinazolines, Gene Library, Fusion Proteins, bcr-abl, Polymerase Chain Reaction, Proto-Oncogene Proteins c-abl, Sequence Analysis, RNA, DNA, Complementary, Gene Dosage, Proto-Oncogene Proteins c-met, Cell Line, Tumor, Epithelial-Mesenchymal Transition, DNA Barcoding, Taxonomic
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