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- Title
Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer.
- Authors
Aissa, Alexandre F.; Islam, Abul B. M. M. K.; Ariss, Majd M.; Go, Cammille C.; Rader, Alexandra E.; Conrardy, Ryan D.; Gajda, Alexa M.; Rubio-Perez, Carlota; Valyi-Nagy, Klara; Pasquinelli, Mary; Feldman, Lawrence E.; Green, Stefan J.; Lopez-Bigas, Nuria; Frolov, Maxim V.; Benevolenskaya, Elizaveta V.
- 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. It has been proposed that resistance to targeted therapies in non-small cell lung carcinoma (NSCLC) is due to a nonhomogeneous cell population. Here the authors analyse preclinical NSCLC models using single-cell RNA-seq and identify drug tolerant cell states and subpopulations, as well as associated genes.
- Subjects
DRUG tolerance; SMALL molecules; PROTEIN-tyrosine kinases; CANCER treatment; EPIDERMAL growth factor receptors; CELL populations
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-21884-z