title: Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, USA.|Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ramirez
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, USA.|Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Satwik
authors.initials: S
authors.lastname: Rajaram
authors.affiliation: Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Steininger
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Osipchuk
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Maike A
authors.initials: MA
authors.lastname: Roth
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Leanna S
authors.initials: LS
authors.lastname: Morinishi
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Evans
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Weiyue
authors.initials: W
authors.lastname: Ji
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Chien-Hsiang
authors.initials: CH
authors.lastname: Hsu
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Thurley
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Anwu
authors.initials: A
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Prasad R
authors.initials: PR
authors.lastname: Koduru
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Posner
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, USA.|Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Lani F
authors.initials: LF
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, USA.|Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Altschuler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000069347:Erlotinib Hydrochloride