2. Academic Validation
  3. Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

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

  • Cancer Discov. 2022 Apr 1;12(4):1022-1045. doi: 10.1158/2159-8290.CD-20-1265.
Chewei Anderson Chang  # 1 2,  Jayu Jen  # 3,  Shaowen Jiang 4,  Azin Sayad 2,  Arvind Singh Mer 1 2,  Kevin R Brown 5,  Allison M L Nixon 5,  Avantika Dhabaria 6 7,  Kwan Ho Tang 2 3,  David Venet 8,  Christos Sotiriou 8 9,  Jiehui Deng 3 10,  Kwok-Kin Wong 3 10,  Sylvia Adams 3 10,  Peter Meyn 11,  Adriana Heguy 11,  Jane A Skok 3 12,  Aristotelis Tsirigos 3 4 12,  Beatrix Ueberheide 6 7,  Jason Moffat 5 13 14,  Abhyudai Singh 15 16,  Benjamin Haibe-Kains 1 2 17 18 19,  Alireza Khodadadi-Jamayran 4,  Benjamin G Neel 1 2 3 10
Affiliations

Affiliations

  • 1 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 2 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 3 Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York University Langone Health, New York, New York.
  • 4 Applied Bioinformatics Laboratories, Office of Science and Research, NYU Grossman School of Medicine, New York University Langone Health, New York, New York.
  • 5 Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
  • 6 Proteomics Laboratory, Division of Advanced Research and Technology, NYU Grossman School of Medicine, New York University Langone Health, New York, New York.
  • 7 Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York University Langone Health, New York, New York.
  • 8 Breast Cancer Translational Research Laboratory, Institut Jules Bordet Brussels and Université Libre de Bruxelles (ULB), Belgium.
  • 9 Medical Oncology Department, Institut Jules Bordet Brussels and Université Libre de Bruxelles (ULB), Belgium.
  • 10 Division of Hematology and Medical Oncology, Department of Medicine, Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York University Langone Health, New York, New York.
  • 11 Genome Technology Center, Division of Advanced Research Technologies, NYU Grossman School of Medicine, New York University Langone Health, New York, New York.
  • 12 Department of Pathology, NYU Grossman School of Medicine, New York University Langone Health, New York, New York.
  • 13 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 14 Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
  • 15 Department of Electrical and Computer Engineering, University of Delaware, Newark, Delaware.
  • 16 Department of Biomedical Engineering, University of Delaware, Newark, Delaware.
  • 17 Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
  • 18 Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • 19 Vector Institute for Artificial Intelligence, Toronto, Ontario, Canada.
  • # Contributed equally.
PMID: 34911733 DOI: 10.1158/2159-8290.CD-20-1265
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16069
    99.82%, HER2 Inhibitor