The Emergence of Diverse Drug-Resistance Mechanisms from Drug Tolerant Cancer Persister Cells

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.