Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells
Open accessAbstract
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.
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Altschuler and colleagues derived a panel of erlotinib-resistant cell lines from single PC9 drug-tolerant cells that recapitulated multiple mechanisms of acquired resistance observed in the clinic, including EGFRT790M and MET amplification.
“Similar conclusions were reached by Altschuler and colleagues, who derived a panel of erlotinib-resistant cell lines from single PC9 drug-tolerant cells. Collectively, these resistant cells recapitulated multiple mechanisms of acquired resistance observed in the clinic, including EGFRT790M and MET amplification [26].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [26]
Clinical mechanisms of acquired resistance can occur by evolution of drug-tolerant persister cells during long term drug exposure.
“Subsequently, work by our group and others showed that clinical mechanisms of acquired resistance can occur by evolution of drug-tolerant persister cells during long term drug exposure [25,26].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [26]
The drug-tolerant persister state may comprise a reservoir of cells from which heterogeneous drug-resistance mechanisms can evolve.
“Thus, these studies suggest that the drug-tolerant persister state may comprise a reservoir of cells from which heterogeneous drug-resistance mechanisms can evolve.”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [26]
The drug-tolerant persister state can serve as a cellular reservoir from which clones that evolve bona fide drug-resistance mechanisms can emerge.
“These tumor subpopulations can evade strong selective drug pressure by entering this drug-tolerant “persister” state which can then serve as a cellular reservoir from which clones that evolve bona fide drug-resistance mechanisms can emerge [25,26].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [26]
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References 42 · Cited by 581
- Authors
- 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.
- Affiliations
- University of California, San Francisco (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Wu, Lani F.
- Altschuler, Steven J.
- ORCID
- Venue
- Nature Communications
- Published
- 2016-02-19
- Volume
- 7
- Issue
- 1
- Pages
- 10690-10690
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4762880
- OpenAlex
- W2275679174
- Cited by
- 581
- References
- 42
- Citations by year
- 2026: 49 · 2025: 56 · 2024: 62 · 2023: 56 · 2022: 78 · 2021: 68 · 2020: 66 · 2019: 52 · 2018: 46 · 2017: 33 · 2016: 14
- FWCI
- 43.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Welch Foundation (I-1644)
- Cancer Prevention and Research Institute of Texas (RP110708-C2, RP110708)
- National Institutes of Health (NIH-R01)
- University of Texas MD Anderson Cancer Center
- University of California, San Francisco
- National Cancer Institute (CA185404, R01CA133253, R01CA185404, P30CA142543)
- National Institute of General Medical Sciences (T32GM008284, T32GM067547)
- National Institute of Biomedical Imaging and Bioengineering (T32EB009383)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- drug-tolerant persister cells, drug resistance mechanisms, erlotinib resistance, EGFR, lung cancer, tumor cell subpopulations
- MeSH terms
- Erlotinib Hydrochloride, Animals, Antineoplastic Agents, Humans, Lung Neoplasms, Mutation, Tumor Cells, Cultured, Drug Resistance, Neoplasm, Cell Line, Tumor, Mice
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