Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer
Open accessAbstract
Intratumoral heterogeneity in cancers arises from genomic instability and epigenomic plasticity and is associated with resistance to cytotoxic and targeted therapies. We show here that cell-state heterogeneity, defined by differentiation-state marker expression, is high in triple-negative and basal-like breast cancer subtypes, and that drug tolerant persister (DTP) cell populations with altered marker expression emerge during treatment with a wide range of pathway-targeted therapeutic compounds. We show that MEK and PI3K/mTOR inhibitor-driven DTP states arise through distinct cell-state transitions rather than by Darwinian selection of preexisting subpopulations, and that these transitions involve dynamic remodeling of open chromatin architecture. Increased activity of many chromatin modifier enzymes, including BRD4, is observed in DTP cells. Co-treatment with the PI3K/mTOR inhibitor BEZ235 and the BET inhibitor JQ1 prevents changes to the open chromatin architecture, inhibits the acquisition of a DTP state, and results in robust cell death in vitro and xenograft regression in vivo.
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BET proteins facilitate chromatin remodeling and transcriptional adaptation necessary for establishing the DTP state in response to MEK and PI3K inhibitors in breast cancer models, which can be prevented by the BET inhibitor JQ1.
“Several studies have revealed that BET proteins facilitate chromatin remodeling and transcriptional adaptation necessary for establishing the DTP state in response to MEK and PI3K inhibitors in breast cancer models, which can be prevented by the BET inhibitor JQ1 [66,74].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [66]
Risom et al. showed that a MEK and PI3K/mTOR inhibitor-driven drug-tolerant persistent state in breast cancer arises through distinct cell-state transitions which involves dynamic remodeling of open chromatin architecture, in contrast to simple Darwinian selection of pre-existing subpopulations.
“Risom et al. showed that a MEK and PI3K/mTOR inhibitor-driven drug-tolerant persistent state in breast cancer arises through distinct cell-state transitions which involves dynamic remodeling of open chromatin architecture [66], in contrast to simple Darwinian selection of pre-existing subpopulations.”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [66]
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- Authors
- Risom, T., Langer, E. M., Chapman, M. P., Rantala, J., Fields, A. J., Boniface, C., Alvarez, M. J., Kendsersky, N. D., Pelz, C. R., Johnson-Camacho, K., Dobrolecki, L. E., Chin, K., Aswani, A. J., Wang, N. J., Califano, A., Lewis, M. T., Tomlin, C. J., Spellman, P. T., Adey, A., Gray, J. W., & Sears, R. C.
- Affiliations
- Oregon Health & Science University (US)
- University of California, Berkeley (US)
- DarwinHealth (United States) (US)
- Baylor College of Medicine (US)
- Corresponding author
- Gray, Joe W.
- Sears, Rosalie C.
- ORCID
- Risom, Tyler
- Langer, Ellen M.
- Chapman, Margaret P.
- Rantala, Juha
- Fields, Andrew J.
- Boniface, Christopher
- Alvarez, Mariano J.
- Kendsersky, Nicholas D.
- Pelz, Carl R.
- Dobrolecki, Lacey E.
- Chin, Koei
- Aswani, Anil J.
- Califano, Andrea
- Lewis, Michael T.
- Tomlin, Claire J.
- Spellman, Paul T.
- Adey, Andrew
- Gray, Joe W.
- Sears, Rosalie C.
- Venue
- Nature Communications
- Published
- 2018-09-19
- Volume
- 9
- Issue
- 1
- Pages
- 3815-3815
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6145927
- OpenAlex
- W2891378535
- Cited by
- 174
- References
- 75
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 19 · 2023: 30 · 2022: 23 · 2021: 36 · 2020: 21 · 2019: 18 · 2018: 3 · 2014: 1
- FWCI
- 7.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (5T32GM071338-09, CA209988, CA112970, CA129040, CA100855)
- U.S. Department of Defense (BC103625)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- basal-like breast cancer, triple-negative breast cancer, drug resistance, intratumoral heterogeneity, drug-tolerant persister cells, cell state transitions, MEK inhibitors, PI3K/mTOR inhibitors, BEZ235, JQ1, BET inhibitors, BRD4, chromatin remodeling, epigenetic plasticity
- MeSH terms
- Cell Plasticity, Animals, Antineoplastic Agents, Azepines, Breast Neoplasms, Cell Differentiation, Chromatin, Female, Humans, Triazoles, Mice, SCID, Mice, Inbred NOD, Drug Resistance, Neoplasm, Cell Line, Tumor, Molecular Targeted Therapy, Triple Negative Breast Neoplasms
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