Studying clonal dynamics in response to cancer therapy using high-complexity barcoding.

Autor:	Bhang HE; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Ruddy DA; Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Krishnamurthy Radhakrishna V; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Caushi JX; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Zhao R; 1] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA., Hims MM; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Singh AP; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Kao I; Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Rakiec D; Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Shaw P; Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Balak M; Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Raza A; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Ackley E; Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Keen N; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Schlabach MR; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Palmer M; Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Leary RJ; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Chiang DY; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Sellers WR; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Michor F; 1] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA., Cooke VG; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Korn JM; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA., Stegmeier F; Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	Nature medicine [Nat Med] 2015 May; Vol. 21 (5), pp. 440-8. Date of Electronic Publication: 2015 Apr 13.
DOI:	10.1038/nm.3841
Abstrakt:	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.
Databáze:	MEDLINE
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