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, Steven J. Altschuler

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134 Scopus citations

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.

Original languageEnglish (US)
Article number10690
JournalNature communications
Volume7
DOIs
StatePublished - Feb 19 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Ramirez, M., Rajaram, S., Steininger, R. J., Osipchuk, D., Roth, M. A., Morinishi, L. S., Evans, L., Ji, W., Hsu, C. H., Thurley, K., Wei, S., Zhou, A., Koduru, P. R., Posner, B. A., Wu, L. F., & Altschuler, S. J. (2016). Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nature communications, 7, [10690]. https://doi.org/10.1038/ncomms10690