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

Michael Ramirez, Satwik Rajaram, Robert J. Steininger, Daria Osipchuk, Maike A. Roth, Leanna S. Morinishi, Louise Evans, Weiyue Ji, Chien-Hsiang Hsu, Kevin Thurley, Shuguang Wei, Anwu Zhou, Prasad R. Koduru, Bruce A. Posner, Lani F. Wu () and Steven J. Altschuler ()
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Michael Ramirez: University of California, San Francisco
Satwik Rajaram: University of California, San Francisco
Robert J. Steininger: Green Center for Systems Biology, University of Texas Southwestern Medical Center
Daria Osipchuk: University of California, San Francisco
Maike A. Roth: University of California, San Francisco
Leanna S. Morinishi: University of California, San Francisco
Louise Evans: University of California, San Francisco
Weiyue Ji: University of California, San Francisco
Chien-Hsiang Hsu: University of California, San Francisco
Kevin Thurley: University of California, San Francisco
Shuguang Wei: University of Texas Southwestern Medical Center
Anwu Zhou: University of Texas Southwestern Medical Center
Prasad R. Koduru: University of Texas Southwestern Medical Center
Bruce A. Posner: University of Texas Southwestern Medical Center
Lani F. Wu: University of California, San Francisco
Steven J. Altschuler: University of California, San Francisco

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10690

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