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Cited by 119HER2/EGFR in Cancer ResearchCancer Cells and MetastasisPI3K/AKT/mTOR signaling in cancer

Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

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Chang, Chewei Anderson, Jen, Jayu, Jiang, Shaowen, Sayad, Azin, Mer, Arvind Singh, Brown, Kevin R., Nixon, Allison M.L., Dhabaria, Avantika +16 more·2022·Cancer Discovery
DOI 10.1158/2159-8290.cd-20-1265PMC PMC8983469

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Abstract

Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. “Drug-tolerant persisters” (DTP), a subpopulation of cancer cells that survive via reversible, nongenetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKI) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single-cell RNA sequencing reveals that HER2+ breast cancer cells cycle stochastically through a “pre-DTP” state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting shows that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor–dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation. Significance: DTPs are implicated in resistance to anticancer therapies, but their ontogeny and vulnerabilities remain unclear. We find that HER2 TKI-DTPs emerge from stochastically arising primed cells (“pre-DTPs”) that engage either of two distinct transcriptional programs upon TKI exposure. Our results provide new insights into DTP ontogeny and potential therapeutic vulnerabilities. This article is highlighted in the In This Issue feature, p. 873

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  • In cancer, diapause-like states enable survival under therapeutic pressure and eventually give rise to drug-resistant populations.

    “In cancer, such diapause-like states enable survival under therapeutic pressure and eventually give rise to drug-resistant populations.40,41”

    From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [41]

    The Abstract describes a diapause-enriched pre-persister state that preferentially yields drug-tolerant cells after HER2 inhibitor exposure. The Discussion says persisters survive treatment and can acquire mutations conferring stable resistance, but presents that progression as a possibility, not an inevitable outcome. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Trajectory analysis revealed that Paneth-like cells emerged from a diapause-like drug-tolerant persister (DTP) intermediate (clusters C3-C4).

    “Trajectory analysis further revealed that Paneth-like cells emerged from a diapause-like drug-tolerant persister (DTP) intermediate (clusters C3–C4; Figures 1R, S1Q, and S1R), previously associated with adaptation to therapy-induced stress.40,41”

    From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [41]

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Authors
Chang, C. A., Jen, J., Jiang, S., Sayad, A., Mer, A. S., Brown, K. R., Nixon, A. M. L., Dhabaria, A., Tang, K. H., Venet, D., Sotiriou, C., Deng, J., Wong, K.-K., Adams, S., Meyn, P., Heguy, A., Skok, J. A., Tsirigos, A., Ueberheide, B., Moffat, J., Singh, A., Haibe-Kains, B., Khodadadi-Jamayran, A., & Neel, B. G.
Affiliations
  • 1Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • NYU Langone Health (US)
  • New York University (US)
  • University Health Network (CA)
  • University of Toronto (CA)
  • Université Libre de Bruxelles (BE)
  • 3Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York University Langone Health, New York, New York.
  • University of Delaware (US)
Corresponding author
Neel, Benjamin G.
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2021-12-15
Volume
12
Issue
4
Pages
1022-1045
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-20-1265
PMC
PMC8983469
OpenAlex
W4200132645
Cited by
119
References
7
Citations by year
2026: 17 · 2025: 35 · 2024: 29 · 2023: 21 · 2022: 17
FWCI
6.28
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Cancer Discovery (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
Funders
  • Foundation for the National Institutes of Health (P01CA229086)
  • HHS | NIH | NCI | Basic Research Laboratory (CA59152, GM124446)
  • Government of Ontario (Ontario Research Excellence Fund)
  • Gouvernement du Canada | Canadian Institutes of Health Research (MOP-142375)
Topics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
drug-tolerant persisters, HER2-positive breast cancer, tyrosine kinase inhibitor resistance, cellular senescence, diapause, estrogen receptor, SGK3, PI3K/Akt/mTORC1 pathway, mTORC1 activation, therapeutic vulnerabilities
MeSH terms
Breast Neoplasms, Female, Humans, Signal Transduction, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Cell Line, Tumor

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