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

Michael Ramirez,Weiyue Ji,Bruce A Posner,Louise Evans,Leanna S Morinishi,Maike A Roth,Kevin Thurley,Chien-Hsiang Hsu,Steven J Altschuler,Satwik Rajaram,Prasad R Koduru,Anwu Zhou,Lani F Wu,Robert J Steininger,Daria Osipchuk,Shuguang Wei

doi:10.1038/ncomms10690

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.

Highlights

Cancer therapy has traditionally focused on eliminating fast-growing populations of cells
We chose as our model system the well-studied, epidermal growth factor receptor (EGFR)-addicted non-small cell lung cancer (NSCLC) cell line PC9 for several reasons
Not all NSCLC erlotinib-resistance mechanisms reported in the literature were exhibited by the Persister-derived erlotinibresistant colonies (PERCs); we found no compelling evidence of transformation to small cell lung cancer, epithelial-to-mesenchymal transition or activation of IGF1R, AXL or NFK-B

Summary

Introduction

Cancer therapy has traditionally focused on eliminating fast-growing populations of cells. 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. In response to a variety of strong drug challenges, small subpopulations of cells have been reported to survive by initially entering a drug-tolerant (so-called) ‘persister’ state in which there is little-to-no population growth[8,12]. After long-term treatment (weeks to months) in drug without appreciable growth, a fraction of persisters gain the ability to expand in drug It has been hypothesized, but never demonstrated experimentally, that survival and expansion through a drug-tolerant state could be part of an initial strategy that mediates the acquisition of bona fide, genetically driven, resistance mechanisms[8]. Our results suggest that 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

Methods

Results

Conclusion