The Emergence of Diverse Drug-Resistance Mechanisms from Drug Tolerant Cancer Persister Cells
type: CreativeWork
description: Cancer therapy has traditionally focused on eliminating fast-growing populations of cells, yet a growing body of evidence suggests that small subpopulations of cancer cells can evade strong selective drug pressure by entering a slow-growing "persister" state. 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 and clinical relevance of drug-resistance mechanisms that can expand from a persister bottleneck is unknown. Here, we compared persister-derived, erlotinib-resistant colonies that arose from a single, EGFR-addicted lung cancer cell. We found, using a combination of large-scale drug screening and whole-exome sequencing, that our erlotinib-resistant colonies had 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--from which drug-resistance heterogeneity can emerge.
abstract: Cancer therapy has traditionally focused on eliminating fast-growing populations of cells, yet a growing body of evidence suggests that small subpopulations of cancer cells can evade strong selective drug pressure by entering a slow-growing "persister" state. 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 and clinical relevance of drug-resistance mechanisms that can expand from a persister bottleneck is unknown. Here, we compared persister-derived, erlotinib-resistant colonies that arose from a single, EGFR-addicted lung cancer cell. We found, using a combination of large-scale drug screening and whole-exome sequencing, that our erlotinib-resistant colonies had 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--from which drug-resistance heterogeneity can emerge.
author: Ramirez, Michael Edward
language: en
keywords: Antineoplastic Agents, Drug Resistance, Neoplasm, Erlotinib Hydrochloride, Lung Neoplasms
date published: 2018-01-04T21:09:49Z
date modified: 2026-07-24T05:52:15Z
provider: University of Texas Southwestern Medical Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Texas Southwestern Medical Center

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2152.5/4448