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Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer

Author

Listed:
  • Alexandre F. Aissa

    (University of Illinois at Chicago)

  • Abul B. M. M. K. Islam

    (University of Illinois at Chicago
    University of Dhaka)

  • Majd M. Ariss

    (University of Illinois at Chicago)

  • Cammille C. Go

    (University of Illinois at Chicago)

  • Alexandra E. Rader

    (University of Illinois at Chicago)

  • Ryan D. Conrardy

    (University of Illinois at Chicago)

  • Alexa M. Gajda

    (University of Illinois at Chicago)

  • Carlota Rubio-Perez

    (Biomedical Genomics Lab, Institute for Research in Biomedicine (IRB))

  • Klara Valyi-Nagy

    (University of Illinois at Chicago)

  • Mary Pasquinelli

    (University of Illinois at Chicago)

  • Lawrence E. Feldman

    (University of Illinois at Chicago)

  • Stefan J. Green

    (University of Illinois at Chicago)

  • Nuria Lopez-Bigas

    (Biomedical Genomics Lab, Institute for Research in Biomedicine (IRB))

  • Maxim V. Frolov

    (University of Illinois at Chicago)

  • Elizaveta V. Benevolenskaya

    (University of Illinois at Chicago)

Abstract

Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor tyrosine kinases. However, the duration of clinical response is often limited, and patients ultimately develop drug resistance. Here, we use single-cell RNA sequencing to demonstrate the existence of multiple cancer cell subpopulations within cell lines, xenograft tumors and patient tumors. These subpopulations exhibit epigenetic changes and differential therapeutic sensitivity. Recurrently overrepresented ontologies in genes that are differentially expressed between drug tolerant cell populations and drug sensitive cells include epithelial-to-mesenchymal transition, epithelium development, vesicle mediated transport, drug metabolism and cholesterol homeostasis. We show analysis of identified markers using the LINCS database to predict and functionally validate small molecules that target selected drug tolerant cell populations. In combination with EGFR inhibitors, crizotinib inhibits the emergence of a defined subset of EGFR inhibitor-tolerant clones. In this study, we describe the spectrum of changes associated with drug tolerance and inhibition of specific tolerant cell subpopulations with combination agents.

Suggested Citation

  • Alexandre F. Aissa & Abul B. M. M. K. Islam & Majd M. Ariss & Cammille C. Go & Alexandra E. Rader & Ryan D. Conrardy & Alexa M. Gajda & Carlota Rubio-Perez & Klara Valyi-Nagy & Mary Pasquinelli & Lawr, 2021. "Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer," Nature Communications, Nature, vol. 12(1), pages 1-25, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21884-z
    DOI: 10.1038/s41467-021-21884-z
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    Cited by:

    1. Franziska Haderk & Yu-Ting Chou & Lauren Cech & Celia Fernández-Méndez & Johnny Yu & Victor Olivas & Ismail M. Meraz & Dora Barbosa Rabago & D. Lucas Kerr & Carlos Gomez & David V. Allegakoen & Juan G, 2024. "Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Cristiana Spinelli & Lata Adnani & Brian Meehan & Laura Montermini & Sidong Huang & Minjun Kim & Tamiko Nishimura & Sidney E. Croul & Ichiro Nakano & Yasser Riazalhosseini & Janusz Rak, 2024. "Mesenchymal glioma stem cells trigger vasectasia—distinct neovascularization process stimulated by extracellular vesicles carrying EGFR," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Junyi Chen & Xiaoying Wang & Anjun Ma & Qi-En Wang & Bingqiang Liu & Lang Li & Dong Xu & Qin Ma, 2022. "Deep transfer learning of cancer drug responses by integrating bulk and single-cell RNA-seq data," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Sarah Figarol & Célia Delahaye & Rémi Gence & Aurélia Doussine & Juan Pablo Cerapio & Mathylda Brachais & Claudine Tardy & Nicolas Béry & Raghda Asslan & Jacques Colinge & Jean-Philippe Villemin & Ant, 2024. "Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Michael S. Balzer & Tomohito Doke & Ya-Wen Yang & Daniel L. Aldridge & Hailong Hu & Hung Mai & Dhanunjay Mukhi & Ziyuan Ma & Rojesh Shrestha & Matthew B. Palmer & Christopher A. Hunter & Katalin Suszt, 2022. "Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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