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

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, Lawrence E. Feldman, Stefan J. Green, Nuria Lopez-Bigas, Maxim V. Frolov and Elizaveta V. Benevolenskaya ()
Additional contact information
Alexandre F. Aissa: University of Illinois at Chicago
Abul B. M. M. K. Islam: University of Illinois at Chicago
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

Nature Communications, 2021, vol. 12, issue 1, 1-25

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21884-z

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