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Nat Commun. 2016 Feb 19;7:10690. doi: 10.1038/ncomms10690.

Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells.

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, USA.
2
Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
3
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
4
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

Abstract

Cancer therapy has traditionally focused on eliminating fast-growing populations of cells. Yet, an increasing body of evidence suggests that small subpopulations of cancer cells can evade strong selective drug pressure by entering a 'persister' state of negligible growth. This drug-tolerant state has been hypothesized to be part of an initial strategy towards eventual acquisition of bona fide drug-resistance mechanisms. However, the diversity of drug-resistance mechanisms that can expand from a persister bottleneck is unknown. Here we compare persister-derived, erlotinib-resistant colonies that arose from a single, EGFR-addicted lung cancer cell. We find, using a combination of large-scale drug screening and whole-exome sequencing, that our erlotinib-resistant colonies acquired diverse resistance mechanisms, including the most commonly observed clinical resistance mechanisms. Thus, the drug-tolerant persister state does not limit--and may even provide a latent reservoir of cells for--the emergence of heterogeneous drug-resistance mechanisms.

PMID:
26891683
PMCID:
PMC4762880
DOI:
10.1038/ncomms10690
[Indexed for MEDLINE]
Free PMC Article

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