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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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Bhang HE,Ruddy DA,Krishnamurthy Radhakrishna V,Caushi JX,Zhao R,Hims MM,Singh AP,Kao I,Rakiec D,Shaw P,Balak M,Raza A,Ackley E,Keen N,Schlabach MR,Palmer M,Leary RJ,Chiang DY,Sellers WR,Michor F,Cooke VG,Korn JM

doi

10.1038/nm.3841

subject

Has Abstract

pub_date

2015-05-01 00:00:00

pages

440-8

issue

5

eissn

1078-8956

issn

1546-170X

pii

nm.3841

journal_volume

21

pub_type

杂志文章

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